Allogene Therapeutics Conference Call - ALLOGENE THERAPEUTICS INC

Hello, thank you for standing by and welcome to Allogene Therapeutics conference call. After the speaker's presentation, there will be a question and answer session. At this time, all participants are in a listen-only mode. To ask a question during the session, you will need to press star 1-1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be aware that today's conference call is being recorded. I would now like to turn the call over to Christine Casciano, Chief Corporate Affairs and Brand Strategy Officer. Ms. Casciato, please go ahead. Thank you, Operator, and welcome everyone to Allogene's webinar focused on our first clinical findings from the Phase 1 Resolution Trial with Allo329. Earlier this morning, Allogene issued a press release that provided an overview of this data. The poster presentation from ACR Convergence will occur after this call. The press release, presentation, and poster associated with this data will be available on our website. Today, we are joined by Dr. Zachary Roberts, President and Chief Executive Officer, and Dr. Vivek Nagarajah of Mayo Clinic Arizona, both of whom will be able for questions following today's presentation. During today's call, we will be making certain forward-looking statements, including statements regarding the development of ALLO329, its potential safety, efficacy, tolerability, durability and its potential to provide clinical benefit in autoimmune diseases. These statements may also address the potential to reduce or eliminate lymphodepleting chemotherapy, the relationship between B-cell depletion and clinical response, and the significance of findings across different dose levels and conditioning approaches. We may also discuss continued dose escalation, future clinical data updates, and plans for advancing the resolution program. 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. There are caution not to place undue reliance on these forward-looking statements when Allogene disclaims any obligation to update these statements. I'll now turn the call over to Zach. Thanks, Christine. Good morning, everybody. So, today marks an important milestone for OWL 329, which is, of course, our first clinical and translational data from the ongoing resolution study. From the start, our objective has been to develop an allogeneic CAR-T specifically for autoimmune disease, in which we prioritize safety, clinical benefit, and aim to reduce the treatment burden for this group of patients. On today's call, we will be joined by Dr. Vivek Nagarajah, who is chair of rheumatology at Mayo Clinic Arizona, as well as an investigator on the study. He brings firsthand experience treating patients in resolution and deep experience in scleroderma. As I discussed on our quarterly call, when we began thinking about our approach to allogeneic CAR T in 2024, we really started to think from the patients and then work backwards. We asked what was preventing patients from benefiting from CAR T and how could we use the distinct advantages of an off-the-shelf platform to overcome those barriers? That thinking became particularly important in autoimmune disease, where these patients often live with chronic conditions for many years, making the balance between therapeutic benefit, treatment risk, and burden fundamentally different from that in oncology. At the end of the day, we didn't want to simply repurpose an oncology CAR-T. We knew that we needed a different product to treat a different group of patients, so we developed a therapy that met the needs of patients specifically with autoimmune diseases, and of course, when treating these patients, safety is at the center of all of the decisions that we've been making. So that philosophy has shaped the design of the Allo329 product, as well as the resolution trial itself. So as we were developing the Alloo329, we made three deliberate choices that would make this a differentiated product. First, of course, it's off the shelf. So scalable manufacturing available for all the patients in this very large group of diseases and with high unmet need, that it is a dual targeting car, the first ever to target both CD19 and CD70, and particularly inclusion of that CD70 as our dagger technology. So Allo329 with this design targets both CD90 positive B cells as well as CD70 positive activated T cells, both of which are believed to contribute to autoimmune disease. Additionally, because that dagger, the CD70 molecule, is designed to address the immune rejection of allogeneic CAR T-cells, we believe that this molecule, the PD70 CAR, can actually help reduce or even eliminate the need for chemotherapy that is traditionally required before treatment with CAR T cells. Ultimately, the objective of this program is to deliver meaningful clinical benefit without introducing unnecessary treatment and complexity, treatment risk and complexity, and to create a therapy that could be more practical for physicians and patients to embrace. So coming to the study itself, we deliberately designed the study to evaluate multiple dose levels of CAR-T. So five are featured in the design of the study. And then critically, we also created a parallel dose escalation pathway across three different lymphoid depletion approaches, no lymphoid completion at all. Cytoxan alone and Flucide. You'll see the data organized around these three lymphodepletion approaches. The design of this trial allows us to ask an important question. So first, how much of the treatment of benefit and safety, for that matter, comes from the CAR-T itself? And secondly, how much lymphodepletion is actually needed, if any? Okay, on slide seven, we feature a little bit of data about around the Dagger technology itself. So traditionally, lymphodepleting chemotherapy has played an important role in CAR-T, in part specifically in allocartes, in suppressing the patient's immune system to allow the infused cells to expand and persist. But that chemotherapy, of course, always brings toxicity, no matter what, whether it's Flucide, whether it's Cytoxan alone, it adds to the overall toxicity burden of CAR-T cells in autoimmune disease, but also in oncology. And in the worst case, these combination chemotherapy regimens can lead to prolonged immunosuppressions of both B cells and T cells, and thereby adding to the overburden of CAR T, particularly in the context of opportunistic infection. The Dagger molecule was designed to address a fundamental challenge in allogeneic CAR T. Can we use this product design feature to reject the CAR T cells by the patient's own immune system, and thereby sort of doing the job of the lymphodepletion? That is the goal of the DAG. And so the bit of data that's shown on the screen right now is modeled in mice, in where we have taken mice in which we mimicked a lymphodepleted state versus a non-lymphodeplated state, and then treated these patients with either, these mice with either a CD19 CAR or an ALLO329, CD19, CD70 CAR. And in the case of the mice that were mimicked to have lymphodipletian, we saw great expansion and persistence of the CD19CAR, and some, but somewhat less, expansion and persistence of ALLO329. Paradoxically, in a non-lymphodiplated mouse, we Saw rapid rejection of CD19CAR, but actually 10 to 20-fold better expansion and persistence of allo-329, thereby indicating that the potency of an allo response in mice, as we have seen in our clinical program with allo 316, actually engenders better cellular kinetics. So this is the biology that is baked into the design of alloe-328. The question is now whether that advantage can translate into meaningful clinical activity with less chemotherapy and therefore a potentially more favorable treatment experience for patients and their physicians. So, moving on to slide eight now, with that background, let's turn to what we're actually learning in the first patients treated with ALLO329. Overall, there are three things that I want to focus on. First, of course, as a phase one first in humans, the emerging safety profile, then the clinical improvements we're seeing in patients with scleroderma, and then finally, what can we learn from the translational data that we've developed so far. And I'll have with me today Dr. Nagaraja, who I'll turn to from time to time to help provide some additional explanation or color on what the findings that I'm sharing mean. Okay, so slide 10, sorry, slide 9. All right, so this is a familiar cartoon to many. So this is a first-in-human phase 1 dose escalation trial evaluating allo-329 and scleroderma, lupus, and inflammatory myositis. The design of the study allows us to evaluate different cell doses and conditioning strategies while beginning to distinguish the effects of CAR-T distinct from the effects caused by the chemotherapy itself. The data that we're presenting today represent only the first two dose levels with no LD and FC-based LD and the first three dose levels for CY alone with enrollments and dose escalation continuing. So overall, we're still pretty early in the dose escalation of the resolution study, and already we're beginning to see some interesting findings, both on the safety and on the efficacy side, that allow us to begin to answer some important questions about how this treatment could be further optimized and then widely deployed. On slide 10, this is the consort diagram of what we'll be discussing today. So overall, by the time the data caught off, we had 18 patients who had been enrolled and infused with ALLO329. This represents the safety analysis set, so we'll be covering safety on all 18 of these patients. And then you can see in today's presentation, this being a first-come, first-served basket study, most of the patients came in with diffuse cutaneous scleroderma, so very little involvement by lung, mostly skin findings in these patients. You can see those broken down across the three lymphodepletion regimens, no LD, Psi alone, and flu Psi. Notably, the others that you see enrolled there that will not be featured for efficacy today will be considered for future presentations. And so, the scleroderma cohort, given the fact that we were starting with TAN, had a good mix of LD regimens and cell doses, which is allowing us to shed a bit of light into the role of lymphodepretion as well as the dose escalation of the cells. Okay. On slide 11, getting into the data now. So, the early safety data shows a favorable tolerability profile. And, of course, this being a phase one, this is the primary endpoint of this trial at this point is the rate of dose-limiting toxicities. And you can see there across the top line, we do not have any dose-limited toxicities observed to date. Around these 18 patients, we've also seen no IECHS, no ICANS, no graft-versus-host disease, and no grade 3 or higher CRS. We did have four cases of CRS, all grade 1 or 2. And importantly, no patients in the no lymphodipletian cohorts experienced treatment-emergent adverse events greater than grade 2. And importantly if you look at that column of no LD, we saw no infections of any kind or prolonged cypenias in the patients who received no chemotherapy-based lymphodipletia. Again, highlighting the value of de-intensifying the lymphodepletia regimen given to these patients with autoimmune diseases. So we recognize that these are early safety results, but so far so good. We're very pleased with the safety profile observed to date, and particularly given our deliberate efforts to minimize the toxicity burden, and particular in light of some of the news events from the summer indicating rates of high-grade toxicities that have led to study pauses with other products. So now I'm going to turn to Dr. Nagaraja and ask, so Dr. Nagaraj, when you see this safety profile, what stands out to you? I think with any new investigational therapy, particularly with cell therapy and CAR-T, I feel very reassured by the fact that most of what we are seeing are grade one or two CRS. The very fact that there's no higher grade CRS or ICANNs or ICHS makes me reassured about the product. Even with the phase one study with our complex disease population, safety to me and our rheumatologists and community is paramount as we go into efficacy. We certainly would like to see safety more. So this is something that I'm reassured. Okay. And how important is safety as you're considering a novel therapy such as allo329 for patients with scleroderma? Yeah, I'll take a 15-second explanation to say that scleroterma is a rare disease. It's an orphan disease. And it's a complex and serious and complex autoimmune disease, not only affecting one organ, the skin, but can affect multiple internal organs. So, you can understand by that that these are patients with a complex disease, and in such a rare, complex condition that doesn't have, you know, many FDA-approved treatments, particularly none for the skin. Safety is paramount, and that's what makes me confident about the safety data. Great. Okay. So, let's move to slide 12. Okay. These are the 10 patients with cutaneous sclerosis or scleroderma that we'll be featuring today for efficacy. So as Dr. Nagarajan just pointed out, scleroterma is a particularly devastating autoimmune disease, very few effective treatments, particularly for the skin, as he pointed out, and there's potential for progressive damage affecting multiple organ systems and multiple aspects of a patient's life. The patients in the study so far came in with substantial skin involvement, prior exposure, as you can see there from the treatment column, to multiple different disease-modifying drugs, many of which carry pretty significant toxicity. Importantly, all the patients in the resolution study, whether they were enrolled with sclerosis or other, stopped their background treatment prior to initiation of the study-specific therapy. So if they were getting lymphodipletian, they stopped before they got lymphodipletian. And in the case of no lymphodempletian, They stopped before They received allo-329. But before sort of getting into the responses that we saw in these patients, it's important to understand who these patients are and what meaningful improvement looks like in clinical practice to somebody like Dr. Nagaraja. So Dr.Nagaraja, can you help put this patient population in context? What kinds of the patients do you typically see with progressive scleroderma and what options are available for their disease if it continues to progress despite treatment? Sure. No, thank you. That's a great question. So to put patients with progressive scleroderma, we call progression primarily from two key areas. One is the skin, the other is the lung, but it's not limited to that. People can have other aspects of the disease, including sometimes muscle inflammation, inflammation in the heart, et cetera. When one of the biggest challenges is, you know, A, people coming to see us on time. So the referral is important. And luckily, scleroderma centers and education has helped that. The second is not only referral, but early recognition that this person might progress. And the knowledge of that has improved a great deal that has helped to enrich many of these trials with those select group of patients. and treatment response to me and to my patients is not only about getting the skin softer, but also helping them improve the range of motion in the hands and other joints because they tend to have quite significant contractures and to also help with the breathing when the lung is involved. Okay, so how important is the range of disease duration here? How long have these folks had scleroderma? How important is that as we think about these patients? And then also, can you comment on their prior therapies and whether this is typical, what – you know, just provide some color on these prior regimens in these patients. Sure. scleroderma is one of the only autoimmune rheumatic diseases where disease duration is of paramount importance and we have good natural history studies. When we enrich patients to a given trial, we like to see those with early disease with a very diffuse form of skin involvement because they are the patients who might also tend to have a higher risk of rapid progression, not only of the skin, but sometimes early, many a time, early involvement of the internal organs. So from that lens, when I see our patient population, our disease duration range from anywhere as little as 15 months to anything as far out as 84 months. So the median disease duration is about, I would say, two years. It's 24 to 28 months. So it's a pretty early disease cohort, and that's been appropriately chosen for recruitment in this trial. The second thing is that certain antibodies do play a role in progression of either the skin, like for example, the RNA polymerase 3, what's called the Pol 3 on the slide, or the SCL70, which is more with the lung, but sometimes also with the skin. We do have rare case of patients with RNP centromere antibodies who do have a risk of progressive disease. And these have all been appropriately involved. So this is the right population to study. The third thing is pertaining to the disease manifestations, which you see on the far column on the right, where you have a multitude of manifestations or features in these patients, which is, to me, who sees scleroderma day in and day out is not surprising. And that's also representative of our usual trial population where we could see an effect. Coming last to treatment, besides a couple of treatments that have been approved for sclerotoma lung disease, which mainly help in preventing progression of the lung, we really don't have anything for the skin. And you can see a common factor called MMF or mycophenolate, which is pretty much a standard of care to start with. But most of the patients at least have tried and failed two medications, some of them up to five medications. You can see that this is a treatment refractory population that we are taking on for a trial to really show a change and an impact. So, those are my kind of length and context of what I feel about this cohort. Excellent. I think that puts this all in great perspective. So with that, let's move on to this slide 13 and start talking about some efficacy. So these are early findings, of course, and we've arranged the data in a way that I think, really will help the audience interpret what we're seeing. So, while we appreciate also that the follow-up time varies, and then, of course, the results are preliminary, we did observe clinical improvement across all three conditioning approaches, including patients critically who received no lymphoidal pleading chemotherapy at all, providing strong evidence that the improvement that we're observing is actually attributable to ALLO329, specifically as it relates to the skin, which is what we're focusing on in this slide. So, improvements to the modified Rodman skin score, or MRSS, were seen very early, and I've been told by rheumatologists that this is actually quite interesting. As soon as day 14, we see improvements in the skin score. Eight of 10 patients achieved and maintained a five-point minimal clinically important difference, or MCID, which you see on the screen, with several experiencing substantially greater reductions of 10 points or more. And what we find especially encouraging is that these responses are occurring early in dose escalation, even without the conventional chemotherapy traditionally associated with CAR-T. So I'm going to go back to you, Dr. Nagaraja. Can you explain what a 5 or a 10-point reduction in MRSS actually means for a patient, and how does the speed of improvement compare with what you typically see using the existing treatments that you use in your clinic every day? I'll preface this by starting and very briefly saying what is MRSS. It refers to something called modified Rodman skin score, where we methodically, consistently perform skin thickness assessment in 17 body areas. And in each area, we score from zero to three. And summatively, it adds up to a scale of zero to 51. Zero, lower the score, better it is. zero being no skin thickening and 51 the the thickest or hardest it can get so um when we quickly look through what are the skin scores in most of these patients they all came with pretty high skin scores to start with at least most of them except for one where it was indication more for the lung usually with our traditional treatments that we use for standard of care the thing I tell patients is as long as the skin is stable over the next three to six months I think that's a good first step and if you do see skin reductions it might happen over a year and I'm taking a pause intentionally for people to digest I'm telling as of now with the standard of care treatments that skin reduction and the score might happen in 6 to 12 months and even for me to do skin assessments from visit to visit i may have about a three point margin of error to see a five to ten point reduction as early as day 14 that's amazing and that's truly amazing because i've actually seen it in the patient in this trial and it's not even me saying it's the patients coming and telling me that the skin is starting to feel better during that time period. So the speed of improvement to me is quite remarkable, and it is life-changing from the patient's perspective. And then one other question for you on this one, and of course, we've broken this out according to lymphodepletion regimen, no LD on the left, psi only in the middle, psi on the right. Can you just reflect on the changes that you can see on the no lymphodepletion regimen here and how that may change how you think about potentially deploying this therapy in your clinic? Absolutely. Dr. Zachary Roberts made a really good point on the fundamental premise of this trial, and that's what excited me about it. The fact that there is an option of a no lymphodeletion arm to actually see the skin score drop even in patients who did not get any lymphodepletion really speaks to the efficacy of the product. Particularly if you see the no lymphodepretion graphs and in the bottom graph where a skin score has dropped down for patient number seven and continues to drop until month three without receiving any lymph depletion. To me, that's really amazing. We always think about giving the least possible medication, least possible side effect producing medication, and the best possible dose. And we know that the more medications or immunomodulatory or immunosuppressive we stack up, the risk goes up. So to not have lymphodepletion, to be able to give just the alochar and see this effect, at least through the preliminary results, that's very positive. Of course, the question is how long does that endure, which we'll have to wait and see. Okay. Thanks. Let's move on to the next slide where we've kind of pulled out a couple of the more interesting responders here. So, these individual cases provide additional understanding and more granularity on how the skin score improved across the multiple body sites that you described, Dr. Nagaraja, as well as now we're overlaying the subjective improvements that are reported using validated patient-reported outcome tools, which are the patient global assessment and then the HAC-DI, or Health Assessment Questionnaire Disability Index. These are commonly used PROs in this disease setting. So in one patient treated with 40 million CAR-T cells without lymphodepletion, that's the patient on the left, obviously the skin scores overall continue to fall. We saw resolution of the digital ulcers and tendon friction rub in this patient. So these are actually objective measures of disease improvement. We found normalization of the skin scores in the hands and the feet and an overall reduction of the MRSS of 14 points between day zero and month three. These changes were accompanied, as one might expect, by steep improvements in their reported improvements, including a normalization of the HAC-DI. On the other side of the screen, the patient treated with 40, sorry, with cyclophosphamide conditioning demonstrated improvement across skin involvement, physical function, and patient reported disease impact as well. For a disease where treatment benefits are often limited to specific manifestations, seeing improvements across multiple dimensions of the disease is particularly encouraging in these two cases. So, Dr. Nagaraja, again, one of the patients shown here is someone that you treated in the study. Can you bring the case to life for us? What was the patient's condition before treatment, and what changes have you observed that may not be fully captured by the data on this slide? Third, it's the patient on the right, patient number two, that I treated. And this is a very high-functioning executive who came to see me and initially had done a lot of reading and had a lot of questions about CAR-T, eligibility, and just generally very interested in Cletrox. And when we had an opportunity and we brought the patient in, the skin score, as you can see in the stack of blocks, was quite high at 20. So 20 is still a high skin score in someone with a very diffused pattern of skin disease. And as you can see, we started seeing the first response as early as day 14, so going from 20 to 12. And then that trend continued down, and at month six, it was down to four. That, to me, was amazing. And not only was that, I think there was self-reported improvement in how much the patient could move the hands. So the hand contractures improved. And we often forget how important our hands are in all the fine motor skills that we have to do on a day-to-day basis. And the patient was able to give me several examples of what they're able to do, including, you know, able to open a bottle while cooking, not having to depend on the partner to have to open that. These are all real day-to-day meaningful examples of change. Not only that, they reported improvement in their levels of tiredness and fatigue, which we see in close to 90% of patients with scleroderma, and that allowed them to be more physically active and was able to return to work in full capacity after the improvement scene. So those are things that obviously we don't capture, except for the fact that you also see the red graph on the right with the HAC-DI, as well as the blue line going down with patient global, where they had a significant drop in terms of how much the burden of the disease was affecting them from a score of 35 down to 15. Now, you do see that at month six, it went up a little bit, but these were for reasons outside scleroderma in the form of some pain in the back. And then can you also comment on how meaningful the improvements in things like digital ulcers and tendon friction rubs are for these patients? Sure. Now, digital ulzers are basically ulcers in the tips of the fingers, also sides of the fingers, or sometimes on the knuckles. And I'll have to share some real examples from patients that I have treated through this trial, I had one person come with such severe skin tightness in the forearm that just because of the tightness, the skin ruptured and opened up as an ulcer that was non-healing for many months. They went on the trial, the ulcer healed, and it never came back. That's a real story. The second, similarly, another person with scleroderma ulcers on the knuckles. And these were, again, because of very tight skin, they could barely be touched. And if they knock onto something by mistake, the pain was through the roof. Those ulcers healed through the trial. And These are things that patients can't make up. These are real things that they're able to see. And this are real things that are meaningful to them. Besides that, tendon friction rubs are basically very stretchy, springy sensation that patients feel in their tendons, particularly those where they also have some level of what we call contractures. In other words, they're not able to fully use their joint because the skin and the tendons are affected. The contracture is improving and ability to move these joints is very meaningful. Lastly, I want to say something about one person who said within about 14 days of treatment, the skin tightness that they had in the neck and the front and the back of the neck, which was preventing them to be able to fully lift their face or neck, that improved quite significantly. And that's something I'm going to be honest. I was not expecting. And what was told was very meaningful to me. and the last one is about physical function and this again I'll quote an example another person who we treated in the car trial came into my office with a walker and actually was brought in on a wheelchair the first time very high skin score in the high 30s and we treated with the car day 14 visit said that I'm able to walk so that doesn't it sounds ridiculous but the person saying I'm able to work itself was it brought a smile to me and then day 28 they said now we are able to we have pushed ourselves to walk a mile or up to 1.2 miles and I can wear my shoe because till then because of skin tightness and swelling they were not able to wear their shoe so these are not just tangible. These are very, very positive feedbacks. We need to see how long it endures in this trial in terms of physical function. Those are terrific stories. Thanks for sharing those. Okay, let's, in the interest of time, move on to the next slide. So this is slide 15, and we can move quickly to this one. So, this looks at the background immunosuppressive therapy, And the takeaway from this is that nine of the 10 patients in this efficacy group remained off their background immunosuppressive therapies from the time that they received their allo329. And the way that this figure is organized is you can see the patient number there that ties back to the table. And then the LD regimen that each patient received. And then the colors of the bars reflect the cell doses that they received. So, Dr. Nagaraja, how important would it be for a patient to achieve a meaningful disease improvement while also remaining off their background immunosuppressive medications? It's pretty huge, right? As in before the advent of any of these trials, we have still been talking about treatment in the long term, and that's quickly followed by a question by our patients, is this treatment for life? And I say, you know, we'll see how things go at each follow-up, but commonly, sometimes, long-term treatment means treatment for Life. So, through the CAR-T trials, particularly through the Allocar, the question people ask is, do I need to go back on the treatments I was on before? It's too early to answer that question because we need to see that enduring effect but how is it important absolutely what do i want what do my patients want that they have a treatment that cures which is a strong word in rheumatology but even if it puts something in remission to the point that they don't need to take long-term immunosuppressive therapy which has its own complications that's a big win so absolutely it means a lot not to be going back on background therapy okay great i mean i certainly i mean just given that list of medications that these patients came in on to to have even a few months off of those meds i'm sure is a big relief and of course you're correct you know with the nine of the ten patients who remain uh at the time the data caught off off of their background immunosuppressive which is what those little arrows mean by the way how long they can stay off, I think, is going to be a really important question. But like I said, even a few months off of mycophenolate, I'm sure, is a relief. All right, let's move on to slide 16, looking at the B cell story. So this one is a very interesting slide. And so this, we actually think, may be one of the more thought-provoking findings in the data set, because it starts to suggest that peripheral B cell dynamics may not be the most important determinant of objective improvement in scleroderma signs and symptoms. And that's provocative because much of the field has focused on achieving complete B-cell depletion as an important indicator and almost a requirement for CAR-T activity and potential efficacy. But because of our study design, we were able to reveal that the death of B-cel depletation, at least in peripheral blood, has much to do, in fact, most to do with the LD intensity. With our product, however, targeting both cd19 and cd70 we observed clinically meaningful improvements in efficacy following regimens that did not yield complete b cell depletion so not only is this kind of interesting by its own right but once again highlights the concept of a therapeutic window with these patients again safety being paramount in this group of patients depletions of b cells particularly for a long period of time is an immune immunosuppressive risk risk. When you add into the fact that conditioning chemotherapy also suppresses T cells, these patients are at reasonably high risk for opportunistic infections, which can be severe and even fatal. So therefore, finding a product and a dose regimen that achieves the desired efficacy while causing as little toxicity as possible is a goal that the field should all be actively pursuing rather than simply perpetuating a belief that a particular biomarker is synonymous with clinical benefit, in this case, complete B-cell aplasia. So, of course, additional translational work is underway as we really dig into some of the more nuanced underpinnings of why we're seeing such marked clinical improvement in these patients, but these early observations raise important questions about what is actually required to achieve a meaningful clinical response. So once again, Dr. Nagaraja, there's been considerable emphasis on achieving complete B-cell depletion with CAR-T. From your perspective, how important is that biomarker relative to what you're seeing clinically in the patient? I think it's really a good question that we are learning a lot through the CAR-D trials. Even prior to the CAR T trials, when we used B-cel depletions medications, particularly rituximab in patients, we've often wondered how much does a low B-cell really translate to improvement in disease activity because we have seen a discordance in many such situations. So when I look at this data and layer it over on the clinical improvements noted, it makes me believe that there is emphasis, but I think there's probably too much emphasis on the requirement of a deeper B cell depletion. I think we should really be carefully looking at what are the clinical efficacy improvements that parallel the B cell depletion. And if there is definitive improvement in the patient sitting in front of us, along with what they are trying to report to us, that to me is more powerful than putting a lot of emphasis on B cell depletion. So I like to see this primarily from a safety standpoint, because we don't want too much B-cell depletions clearly causing a high risk for infections, and that comes with its own set of complications. So those are my thoughts. I would say let's treat the patient in front of us, but also use this data more as a tool, but not as an endpoint. Okay. All right. In the interest of time, let's move to slide 17. And so this will just call out as, you know, as we were preparing this presentation, we reached out to try to better understand how the clinical community of rheumatologists might interpret these findings. Andso three themes in these conversations consistently emerged from these interviews from seven blinded leading rheumatologists and scleroderma experts. The three themes that emerged are the reassuring safety profile, the clinical significance and speed of the improvement to the symptoms, and the potential advantages of seeing activity without lymphodipletion. The clinicians were particularly interested in whether a less intensive regimen could reduce the risk associated with prolonged immunosuppression that is often associated with flu side, and potentially enable a more practical treatment delivery system. While recognizing, again, the early stage of these results, their feedback reinforces the relevance of the clinical questions resolution was, in fact, designed to answer. So, Dr. Nagaraja, how do these reactions that are shown on the screen and those three themes that I just pointed out compare with your own perspective, particularly around the potential benefits for reducing lymphoclination? You know, I see these comments and I'm reassured and also encouraged that these comments and impressions from the KOLs, they align with how I feel. I think the key part is the safety profile as shown, the clinical efficacy as seen, although early, and the fact that there is certainly an opportunity for either reduced or even no lymphodepletion. and I think these are important. These mean a lot for our patients. All right, so thinking about your own practice, you know, and knowing what we know, albeit it's early, so it's, you now, I'm asking you to sort of put your head in the mind that if this profile holds up, which patients would, which scleroderma would you consider for this CAR-T initially and how could the ability to treat without lymphodepletion change that thinking? I think truly evidence-based and being a believer in science, from what I'm seeing at this point, the focus is, of course, people with treatment or rather the initial treatment refractory scleroderma. So that's where I would still base these treatments on. In other words, any person coming with scleroterma the first time I'm seen, we probably are not going to be using CAR-T unless they have already tried some background treatments and have severe disease. But that said, patients are obviously ahead of us. Because of so much information on CAR-D, they really want to be treated up front. So there's going to be a push from the patients that we just need to be sensitive to and take the patient's voice, but really layer that with science and durable data and safety. And I know we're early, but with the safety profile that we've seen, the encouraging efficacy that you just walked through, knowing that this product is available off the shelf, is this something that you could envision using as an outpatient? Absolutely. Why? Because it's an allogeneic product. It's gone through the safety check. It's available off-the-shelf. And then with improving efficacy and safety, this is certainly something that can be translated to an out-patient setting under the purview of both our hematologists as well as our rheumatologists as the care team members. So that's what excites me about that opportunity because this translates to outpatient. We are talking about patients coming in, getting it, and then coming for clinic visits without any need for hospitalization. Okay, great. Let's keep going. So slide 18, I think we frame up a couple of very interesting questions that are emerged from resolution. So, first is, of course, how much lymphodepletion is really necessary, and the second being is, you know, complete peripheral B-cell depletion or aplasia truly required for clinical efficacy, and these are questions that we will be tracking very closely as we get more experience with this product in a greater number of patients and with more follow-up. Moving to slide 19, just to summarize so that we can get to Q&A, so just to wrap up, these first results begin to bring together the deliberate choices that we made in the design of ALLO329 and the resolution study itself. In the 18 patients that we've treated overall, we've observed an encouraging early safety profile, while eight of 10 of the patients who we looked at with the skin-predominant scleroderma achieved and maintained clinically meaningful improvements over several months. Nine of the 10 patients remained off their background immunosuppressive therapy, and clinical activity continued to deepen over time and was observed across all conditioning approaches, including without LD. So, taken together, these findings provide an encouraging early foundation for a potentially differentiated allogeneic CAR-T approach in autoimmune disease. Of course, there's lots more for us to learn, but we're very pleased with the progress of the study so far and what these initial findings may mean for future development. Slide 20 just highlights where we sit in the trial. We've got a catalyst-rich tier ahead of us as we continue dose escalation and begin to expand some of these cohorts and then begin to focus and tailor our development strategy away from a more broad basket design and into more specific focus in certain areas such as scleroderma. So let's move right on to the Q&A now, so we've only got 15 minutes left. So, Christine, is that okay to open the call? Yes, let's do it. As a reminder, to ask a question, please press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press start 1-2. Again, in the interest of time, we ask that you limit yourself to one question. Please stand by while we compile the QA roster. And our first question comes from Michael Yee of UBS. Your line is open. Hey, good morning, guys. This is Matt on for Mike Yee from UBS, congrats on the nice update this morning. I was wondering if you could talk a little bit more about why you believe that a full immune reset is achievable without full B-cell aplasia. And I'm wondering if there's a level we need to hit here or just not the right biomarker. And maybe just on the same topic, how do you feel about the need for CAR-T persistence in order to drive immune reset as well in the context of autoimmune disease? Thanks so much. Thanks, Matt. So, with respect to your first question, can a reset be possible without wiping out the B cells? I think it's an interesting question. I'm not quite sure it's the right question. We still have yet to really define what an immune reset is, and I think probably the best is that, you know, you wipe out your B cells, and then the B cells that come back have a naive phenotype, which is, of course, exactly what you would expect if you wiped out the B cell population. I'll say that there have been some very recent papers showing that the immune reset post CAR T in autoimmune diseases is probably significantly more nuanced than that, and that there are certain rare but very impactful subsets of B and T cells that are likely driving pathogenesis. And so what I think our data indirectly show is that, in fact, there are likely other mechanisms by which these diseases can be improved, whether that's the quote-unquote reset or something else, or rather, you know, between us being able to target both CD19 and CD70, which we know is involved in this, in the biology of scleroderma in the immune niches that don't count and that are not peripheral blood are actually doing that work. So as I mentioned earlier, of course, we are sort of really digging deep here to identify, you know, through biopsies, through other more advanced imaging techniques and so forth to really try to identify where this immune reset is occurring. And so, you Basically, we think that the peripheral blood is probably not the place to be looking. And I'll hasten to add that if we hadn't run resolution the way we did with the three different lymphodipletian regimens, our PD data would look just like everybody else's. We see B-cell aplasia for about 28 days, and then the B-cells come back. And those B- cells that do come back do have a more naive phenotype. But clearly, we're able to get efficacy without doing that, which I think raises the right question. Is that the right thing for us to be striving for in these patients, given the impact to potential infectious risk? Thank you. And our next question comes from Beren Amin of Piper Sandler. Your line is open. Yeah. Hi, guys. Thanks for taking my questions, and congrats on this data update. Maybe for Zach, how many patients and duration of follow-up does the company need to see to assess disease response and choice of lymphodepletion regimen in order to make a go-forward decision on a more expanded trial? So that's the first question. Second question, I think seven of ten patients had esophageal GI manifestations. You know, this tends to be highly prevalent in patients with systemic sclerosis. Any improvements in these patients as it relates to GI symptomology? And then the third question, patient six, I think, is one of the patients that, I guess, needed immunosuppressive therapy. Anything to note on that patient in general? Thanks. Sure, Barron. So first question, how many patients do we need to begin to focus this program? So, I would say that we are having those discussions internally right now. You know, the initial view had been to just continue dose escalation until we, you know, began to see emergent toxicity. I think we're probably softening a bit on that stance, just sort of given the overall shift in the space in the last several months as we've seen some high-profile toxicities really jeopardize programs. So, once again, we're very encouraged with the efficacy that we're seeing. So I think we're in a place now where we can begin to expand certain cohorts and really begin to build an early data set to support a potential phase two design. So I would say we're not ready to make those announcements today, but I would say, you know, in due time, in relative short order, we should be able to make those announcements. So you asked then about the esophageal dysmotility in these patients. So we didn't, you know, that's no objective sort of regimented way that we are assessing the esophageal function in these patients. And we, in general, would be expected to see those manifested in the patient-reported outcomes, which in general have improved across the board here. So I'll have to say, I can't speak to the specific symptoms except for the fact that these patients are generally recording markedly improved overall life and function. But Dr. Nagaraj, any experience directly with esophageal dysmotility in your patients that you can comment on? Sure. So I can allude to one patient who clearly said that within about day 28, they were able to eat their solid foods without having to take a gulp of water with each swallow. And that was something, I'm going to be honest, I didn't expect because we, to this date, don't have any treatments that have meaningfully improved GI involvement, and that's a huge area or a gap. And that's why we also have GI-specific patient-reported outcomes being looked at in this trial, but too early to comment on that. But yeah, that's just one example to share. Great. Thank you. And then you also asked about the patient who did resume their immunosuppressive. I don't have the exact kind of specifics in front of me right now. That's something fear that I can we can update it at a future point as to why that decision was made let's be back do you do you happen to know yeah I think I believe it was due to relapse of the skin in other words the skin score went up around I think it was day 56 or so so it was mainly driven by the increase in the skin's core okay thank you and as a reminder we do ask that you limit yourself to one question. And our next question comes from Tyler Van Buren of TD Cal, and your line is open. Hey, great. Thanks for the informative and thought-provoking webinar. Maybe I'll ask a question to Dr. Nagarajah. I know you touched on this, but how durable do you expect these MRSS improvements to be? And maybe ask another way, I guess, how durable do they need to be with a product profile like this, especially without lymphodepletion? There's quite a bit of variability from patient to patient. The durability of the MRSS, to me, ideally, is it goes down to zero. Is that going to happen? I doubt it, but I'm being very, very, cautiously optimistic. But that said, if the trend is on sequential exam, it continues to trend down to a point that it's meaningfully improved to the patient in terms of any symptoms in the affected skin, any change or return of their skin pigmentation, any improvement in any small nerve fiber kind of symptoms that people might have, including itching, and also any improvement in their joint contractures and hand movement or ability of hand movement. All of these go along with the skin improvement. So I don't want to overemphasize skin score is the only thing we look at, but we take it with the lens of all these other elements. So that is why I think we feel it's a bit early to comment, but the trends are in the right direction. Thank you. And our next question comes from John Newman of Canaccord. Your line is open. Hi there. Thanks for taking my question. Really interesting data this morning. I just had a question. I noticed there were a couple of patients that seem to have ILD involvement. Obviously, you're focused on patients that have primary involvement of the skin, but just curious if a physician could comment on his thoughts for whether this therapy would be appropriate for patients maybe that unfortunately have more involvement in the lungs rather than the skin in the future. John, that's a great question. So maybe I think it's a slightly nuanced answer. So this is a phase one safety efficacy, but at the same time, for people who are coming in with ILD, we're also looking at active ILD from the perspective of the use of this investigation product. those patients, what we are seeing is, you know, we are obtaining baseline lung function tests and follow-up lung function test. And so far, the lung function tasks are either stable or there's not been much of a decline of concern. So lung function stability is what we're seeing at this point. And again, lung tends, for us to comment on lung response, sometimes it takes a little longer than the skin response. That's why we didn't include that data, because it's just too early to say that this is a real impact of the lung, but we're continuing to watch that closely through careful monitoring. Thank you. And our next question comes from Salveen Richter of Goldman Sachs. Your line is open. Hey, this is Mark on for Salvee, and thanks so much for taking our question, and congrats on this great data. I guess you saw, looking at the MRSS score graphs, you saw patients who initially responded and then their responses kind of either paused or maybe even they progressed a little bit and then the responses deepened again afterwards. So what can you tell about the kinetics of Allo329 at this point? And how did the kinetics compare versus competitor autologous or even bispecifics approaches? And sort of does the CD70 mechanism maybe play a role in the genetics here. Thanks. Yeah, thanks, Mark. So I think, you know, the most important thing is that when you're assessing these patients, you're not really dealing with a CT scan where you're sort of have very, very precise objective measurements, right? These are semi-objective assessments of the skin. And so really what you're looking for is not so much, you know, how much do they change one visit to the next, but really do they do they change meaningfully over a period of weeks to months. And I think that our data convincingly shows that. As an allogeneic product, we do not expect these cells to persist indefinitely in these patients. In fact, that's really one of the benefits of this product is that we eventually, even with the dagger, as we saw in our Allo 316 program, eventually they do peter out and disappear. And that actually is a good thing because it allows these patients to get back to a normally functioning immune system. So, you know, our hypothesis at this point is that the CD70 is likely playing a role at the site where the sort of core pathophysiology is occurring here, and that's likely in the tissues themselves. So that both the B-cell depletion as well as modulation of the T-cell compartment through the CD70 is likely what is underpinning the clear efficacy objectives that we're seeing here. So, we're sort of less focused on persistence and more focused on, you know, are we able to fundamentally alter the structure of the immunobiology here that's giving rise to these diseases. So, more to come on that. Thank you. In order to keep this call to an hour, our last question comes from Roger Song of Jefferies. Your line is open. Hi, guys. This is Chacha on for Roger. thanks for squeezing me in, and thanks for the informative call. Can you just give us some more insight into that one patient in the CyFlu cohort who appeared to have the initial MRSS improvement followed by worsening at 1.6? Just wondering if you have any more insights into what drove that trajectory, and was there evidence of loss of CAR T persistence in that case? Yeah, I'll comment on that one, Chacha. So, I think it's a bit early to say, you know, rarely we understand why certain patients remain in durable responses and why they progress. And that applies in areas that we know a lot more about CAR T cells and like oncology. So the specifics of, you know, what happened with that patient, we still are looking into and trying to figure out. I, you Know, there's lots of tantalizing sort of conjecture that I could offer, but, you Now, in the interest of being evidence-based, I'm going to hold off on that and say that we continue to investigate, and if we learn anything about the mechanism of resistance, we will certainly share those. Okay, so I think that was the last question, so I'll just quickly wrap up here. So, you know, just to remind everybody, when we set out with this program, we made deliberate choices to address the needs of the patients living with these chronic autoimmune disorders. The findings that we've shared today, I think, are encouraging across the priorities that we established from the beginning. First, safety. Second, meaningful clinical activity. And then finally, the potential to deliver this profile with a less burdensome treatment approach, ideally without chemotherapy-based lymphodipletion. So over 2027, we look forward to building on these results as we continue the dose escalation and dose expansions and work towards building a potential phase two regimen. Ultimately, we believe that the future of CAR-T will be shaped not only by what these therapies can do, but how we can make them more practical and accessible to patients. And the YALO329 experience today reflects that conviction. Ladies and gentlemen, thank you for your participation in today's conference. This does conclude the program, and you may now log off and disconnect.