Autolus Therapeutics plc ($AUTL)

Good day, everyone, and welcome to the Autolus Investor Event Spotlight on acute lymphoblastic leukemia ALL program. [Operator Instructions] Now it's my pleasure to turn the call over to Amanda Cray. Please proceed.

Thank you, Carmen. Good afternoon or good evening, everyone, and thank you for joining us for today's presentation. With me are Chief Executive Officer, Dr. Christian Itin; and Chief Development Officer, Dr. Matthias Will. Before we get started, I'd like to remind you that during today's call, we will make statements related to our business that are forward-looking under federal securities laws. These may include, but are not limited to, statements regarding the status of development plans, clinical trials and market opportunities for ALL B-cell. These statements are subject to a variety of risks and uncertainties that could cause actual results to differ materially from expectations and reflect our views only as of today. We assume no obligation to update any such forward-looking statements. Also, please note that today's presentation, we will discuss AUCATZYL, which is indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia or BALL. The safety information of AUCATZYL includes a boxed warning for cytokine release syndrome, neurologic toxicities and secondary hematological malignancies. Please refer to the full prescribing information for additional important safety information. With that, I'm pleased to turn it over to Matthias.

Thank you, Amanda. Welcome to our ALL business update day today. I have the pleasure to introduce our team panel of speakers none of them really needs an introduction because the international renowned researchers and clinicians in the field of ALL. But here we go, the first speaker will be Dr. J. Park who is the Director of the adult ALL program and [ Chofcellular ] therapeutics at Memorial Sloan Kettering Cancer Center. Dr. Park was also an investigator on the FedEx trial, and he will speak today about ALL treatment landscape and the unmet medical need. He will be followed by Lori Motley, she is a professor of medicine blood and [ bone ] marrow transplantation and cellular therapeutics at Stanford University. And while she is leading multiple national clinical trials and investigation, she will speak today about the real-world experience ALL B-cell in adult ALL. Dr. [ Mosley ] will be followed by Dr. Eli Jabbour, who is a professor at the Department of Leukemia at MD Anderson Cancer Center in Houston, Texas, and he also serves as the Section Chief of acute lymphoblastic leukemia. Dr. [ Zago ] was also an investigator on the Felix trial, and we'll speak today about the investigator-sponsored trial efforts to evaluate Obicell in frontline adult ALL. And last but not least, we are joined by Dr. Michael Pulsipher, who is the leading pediatric hematologist oncologist at the Huntsman Cancer Center in the University in Utah, and he serves as the Division Chief of [ Beatrix ] Hematology Oncology and also direct major research incites including those with the Children's Oncology Group. He will be speaking today about the pediatric medical unmet need in ALL as well as the ongoing Autolus study catalyst in relapsed/refractory pediatric ALL. And with that, I turn it over to Dr. Park.

Okay. Well, thank you for having me here. So I think we're seeing Slide 5, and then I'll be going very briefly and just highlighting and setting the stage for unmet in real as refractory in adult patients with B-cell ALL Go to the next slide on Slide 6. So adult [ realized ] refractory [ Visa ] ALL. These are -- we have about the roughly 1,800 new relapse refractory cases annually diagnosed in the U.S. 5-year overall survival for those who have relapsed disease with a frontline chemotherapy-based approach is less than 40%. Of the relapsed patients, roughly about 50% of the patients that might be ineligible or decline or allogeneic transplant for different reasons. In a current state and those are the patients we are targeting for CAR T-cell therapy, including those patients who relapse after transplant but in average prior therapy lines of treatment before CAR T cells at [ the ] time of CAR-T cell infusion is about two lines of treatment. The clinical reality to where we stand with an adult B-cell ALL is the first, they are different than pediatric BLL in terms of biology and then outcomes tend to be poor unfortunately, in adult patients compared to children. Median over survival after first relapse is about 6 to 9 months with the prior immunotherapy such as blinatumomab and Inotuzumab, including with bone marrow transplant afterwards. So there is a continued unmet need to develop to target those patients to improve the outcome of relapsed ALL patients. And hopefully, even without the need to proceed to post a CAR-T bone marrow transplant. The next slide, please. For the [ real ] refractory ALL treatment pathway, as we kind of briefly walk through, there's a cascade of attrition, those patients who do get to CAR T. And these are some of the clinical unmet need that we will need to address. But among the realized refraction patients, about half -- a little over half of the patients will achieve a complete remission to blinatumomab or inotuzumab or any salvage therapy. Subset of those patients will then proceed to allogeneic transplant. But not all those patients, again, remain relapsed, and there are patients who don't get too in the transplant, and these are the patients where there is a CAR T cells are applicable and appropriate for those patients. that still leaves a large proportion of the patients who can benefit from the new therapies, such as CAR-T cells. So on the right side, there are some unmet needs in concentrate. We talked about transplant ineligible and we can probably include transplant declining patients as there are more and more patients who are opting for less like altering kind of the treatment options with fewer kind of long-term side effects. The patients who relapsed after blinatumomab and other immunotherapy are still unmet need for those patients, especially now that blinatumomab is incorporated into the frontline treatment. For those patients with Philadelphia chromosome positive ALL, which is subset of a BALL patients who typically do receive concomitant tyrosine kinase inhibitors, TKI for those who do fail those agents unmet need. And lastly, for those patients who have a central nervous system disease, and including extra measure disease or unmet need because those patients also tend to do poorly with the conventional and the monoclonal-based antibody immunotherapy that we do have in chemotherapy. Next slide, please. So in the PLC study, which is a study to study the ALL B-cell for adult patients with the [ bless ] refractory B-cell ALL, it reported 77% over response rate across all patients. And there are subset of the patients who got durable remissions, which means greater than 3 years of a sustained remission without bone marrow transplant after receiving CAR T cell therapy. The patients who had a lower lease burden at the time of CAR T cell infusion did expect better compared to those patients who had a higher disease burden or leukemic cells in their bone marrow. Majority of the responses were MRD-negative, meaning undetectable disease by NGS or flow-cytometry post CAR T cell infusion. And then as we know, the ALL B-cell does have a different CAR T cell binder or the binder to CD19 that is, again, distinguishing itself from the other -- the CD19 CAR T cell that's out there for ALN lymphoma patients. On the right side, it just kind of briefly highlighting that disease burden at infusion is important, which we have seen in other CAR T -- prior CAR T cell studies, including our own previously. It also turns out to be true in the context of FELIX study with an ALL B-cell related refractory patients. The other encouraging finding and trend is that with the 2- and 3-year follow-up that has recently been presented that about roughly about 40% of the patients are remaining in remission with bone marrow transplant after CAR T suggesting that some of this patient -- for some of these patients, CAR T might be a definitive treatment without requiring subsequent bone marrow transplant. And there are some emerging data that has presented the product phenotype, the cell phenotype might matter as much as cell dose achieving a good optimal outcome after CAR T cell infusion. Next slide is where is the current limitations and some of the unmet need currently. The one is the toxicity profile of CAR T cell therapy previously adult ALL patients. suffered the most severe toxicity in terms of cytokine releasing germ neurotoxicity that had limited applying this type of a treatment to older patients, frail patients or patients with different medical comorbidities. Now with obese with a better safety profile with a less severe CRS and eye cancer neurotoxicity rate, it allows application of such therapy to this patient population. CAR-T product business and manufacturing reliability has been pretty successful in the rare setting and post launch which has been encouraging that the majority of the patients are able to get the manufacturing and get delivered in a timely manner for them to receive the treatment. We're also seeing the long-term persistent CAR T cells, which might be correlated with a better durable response, at least in the context of FELIX studies ALL B-cell patients. So that is encouraging trend as we further monitoring the CAR T cell persistence that might be available commercially in the real-world setting. The lastly is the access to even time operational barriers are not just unique to ALL B-cell, it's kind of unique to this field in general, but as we continue to work to increase potentially a pro for patients to receive CAR T and distance and the logistics not being the major reason for these patients not to receive CAR T is a continued area that we should focus on. The next slide. So some of my assessment as to kind of where the field is heading, which will be touched upon in the subsequent presentations is that we have seen the CAR T cell therapy does work very well, get a high initial response rates in the relapsed/refractory setting. But we also do know that T cells -- the CAR T cells do work better when patients receive them in the lower disease burden and earlier line of therapy. So the suggests that CAR T cell therapy might be more efficacious and might be most beneficial in terms of a definitive therapy without needing a bone marrow transplant in the earlier line of frontline setting as a consolidation in MRD-positive or MRD-negative remission in first remission setting. The product biology might be important and suggest that in having a low side effect profile, toxicity profile, CRS and [indiscernible] encouraging, which might be driven by the different biologies, different product phenotype of the cells as we are learning from in ALS setting in the myeloma setting as well. Third is that manufacturing speed reliability are key clinical outcomes for sure for cell therapy because reliability manufacturing is everything for these patients once the cells are taken away and they're receiving back. So a timely manner of receiving a turnaround time and manufacturing success is key. So there has been encouraging sign for this and other products as well too. So lastly is that the single-agent CAR T cell therapy might be efficial for most patients. However, there are some offsets that we do experience relapse after CAR T we're not getting as durable outcomes. And for those patients, I think the future studies will address combination or enhancing further CAR T cell efficacy and product modification. So next, lastly, just ending this what -- how I define the success and what we need for patients are pretty simple, but not always easy to deliver that we needed a powerful in our product to achieve very deep remission for ALL patients for this leukemic patients, but also needs to be safe to deliver to most patients. It also needs to be passed that we can deliver and administer to sell products in a timely patient where we want to deliver and then not limited by the turnaround time. And then lastly, we all want the durable CAR T cells that we don't need a subsequent treatment where maintenance is [indiscernible] bone marrow transplant for this to be kind of a stand-alone treatment? With that, I will turn it over to Dr. [ Motley ] to talk about the next topic.

Thank you, Dr. Park. It's my pleasure to be here today talking about the real-world experience of ALL B-cell. And I will start with the next slide, introducing the audience to our real-world consortium in the United States, studying CAR T cell therapy in adult acute lymphoblastic leukemia. So our consortium has the name of ROCCA. And this group, which is denoted in part on the map, comprises now approximately 50 U.S. CAR T cell therapy leukemia centers. We make up approximately 60% of U.S. commercial products, and that is actually growing as more sites are coming on. And this consortium allows us to study real-world questions regarding new commercially approved cellular therapy [ packs ]. And I think there's really great strength in this approach. The first data presented regarding the use of ALL B-cell in the United States and the commercial thing was presented both at ASH and the Tandem Meeting this past year. we included patients for this initial analysis if they were areas for ALL B-cell between November 18, 2024, and the data cutoff, which was January 8, 2026. Next slide, please. So in this initial analysis, 96 patients were freezed for ALL B-cell within just approximately 1 year included in the consortium. 91 of the 96 the patients received their first infusion of ALL B-cell. The fact that patients that did not receive their infusion were mostly dropped out due to progressive disease and one had lost CD19 expression. Importantly, between first and second dose of ALL B-cell, there was no drop off. So all patients who received first dose went on to receive second dose. A median follow-up at the time of this presentation, which was in February, the Tandem Meeting was 137 days between the first CAR T cell infusion and follow-up, 84 patients were evaluable for day 28 response at this point. And again, these data represented 60% of U.S. commercial is treated in total. So this table shows the cohort of patients who were included in this initial consortium presentation and [ Go ] versus the 127 patients treated on the FELIX trial, which led to the approval of ALL B-cell. I think it's important to recognize that FELIX required certain characteristics and have strict inclusion exclusion just like any clinical trial, whereas patients treated in the real world, in the U.S., really represent an array of different features, and you can see this when comparing the two. The first notable thing is that the patents treated in the rail world are just a bit older and a larger proportion of them are failure with ECOG performance service of two or higher. We also see that patients treated in the real world had increased or more lines of prior therapy. We're more likely to have adverse genetics with the pH like signature. And as you can see here, 68% of patients treating the ROCCA consortium has three or more prior lines of therapy prior to ALL B-cell versus 35 in FELIX. Patients in the real world were highly likely to have received prior blinatumomab, inotuzumab and then the final thing is that the blast percentage was higher for patients treated in the FELIX trial, but that is because one of the inclusion criteria for most of the cohorts of the trial required 5% blast or greater in the bone marrow, whereas in the real world, many of these patients are being treated in a low disease burden setting, as you just heard from Dr. Park. Next slide. The next slide shows the snapshot of the results from this initial real-world cohort of approximately just under 100 patients. And I think it's quite encouraging. I'm going to point out what I find to be most important as a treater. So the first is that this is really the only CAR T cell therapy I'm aware of where the rates of CRS are approximately 50% in the real world. And this is very important because it allows us to treat these patients safely outpatients. There are no instances of higher-grade CRS. The other thing is that if you look at the ICANS, the ICANS rate in the real world with this product, any great ICAN is under 20%. And the vast majority is Grade I or II and really Grade I. So only 17% of patients experience ICANS, which is, again, really sort of bring this outside of the typical CAR T realm and into a more comparable to a very safe treatment that we would give to leukemia patients irrespective of CAR T. And then finally, the efficacy. So we only have day 28 response rates because this is a relatively short follow-up time for this first data cut. But what you can see is that the response rates overall are nearly 95%. Over 70% of patients achieved an MRD-negative CR, which is actually superior to what was seen in the trial. So in summary, we see that in the real word setting, we are treating patients with lower disease burden, but they do tend to be older and more frail. The safety and efficacy look comparable or superior to what was seen in the trial. The safety is really, like I just said, quite phenomenal, 3% high-grade ICANS and 17% overall ICAN. And we believe that the -- based on the FELIX trial that the response rates will only deepen with time. Remember, this is a split dose product. So day 28 is a bit of an early outlook. No. My summary from just looking at this initial data, which you can see on the next slide is that, again, really, this product minimal side effect profile along with the efficacy profile allow us to treat patients who wouldn't otherwise be receiving CAR T cell therapy and also with [ thumb ] centers to treat patients exclusively in the outpatient setting. You can see that we're using ALL B-cell to treat a variety of disease burdens from MRD negative all the way to hybroden disease. And we're also treating patients with both medullary and extramedullary leukemia, which I'll show you on the next slides. And really, our strategy, I think, at many of the high-volume centers is to offer ALL B-cell at least consider ALL B-cell for all patients with relapsed/refractory B-ALL do typically use bridging for patients with high burden disease or high-level MRD. And increasingly, we are not routinely offering transplantation following OVC as we think that a fairly sizable proportion of these patients will be cured with the cellular therapy. On the next two slides, I like to profile to patients who, I think, probably would not have received this therapy in the adult setting if it weren't such a safe and effective CAR T cell. There first and these happen to be both my patients and clinics. So these are real stories. So the first is a 33-year-old woman with Down syndrome. She is minimally verbal patient, but very active with Ph-negative B-ALL that was refractory to three prior lines of therapy. At the time I met her, she went from being a happy, bubbly woman to really being unable to move or do any of the things that gave her pleasure due to her leukemia. We decided to take her to ALL B-cell. She had both extramedullary disease and bone marrow and circulating disease at the time of leukapheresis. She did receive two doses of inotuzumab as bridging and post bridging, she had persistent [ extramedullary ] disease as well as 5% bone marrow involvement. She got standard ALL B-cell both doses were given inpatient due to her developmental needs functional needs. She had great two CRS, got one dose of tocilizumab, one dose of dexamethasone. No ICANS.. And I'm very, very happy to say that her day 28 response assessment showed an MRD negative complete remission. She's now just crossed 1 year. She spends most of her time at Disneyland with her family, which is her favorite place. And she is fully functional. This was absolutely a life-saving treatment for her and she had persistence of CAR T cells with no return in abnormal B-cells. The second patient is another really interesting case of a 26-year old women with multiple relapsed/refractory Ph-positive ALL who had involvement of the spinal cord and with paraplegic at the time that we decided to move forward with ALL B-cell. I will say that we would not have given any other CAR T cell product to this patient, but we did go out on a limb with ALL B-cell given its side effect profile. This patient, as I said, was paraplegic catheter dependent in terms of her bladder function at the time of ALL B-cell. She was also treated inpatient, she had Grade I CRS, which was treated with supportive care only and Grade I ICANS for which we received a single dose of dexamethasone. She also achieved an MRD-negative CR. And on PETMMRI, her spinal lesions have entirely resolved. And she just crossed her 6-month point. She is walking. She is urinating independently. And really, this has been probably one of the biggest success stories I've ever been in my career. Finally, I'd just like to wrap up by again going back to the consortium. So this is a really vibrant and growing community of researchers and clinicians that treat patients with the with CAR T cell therapies. And there's a whole bunch of domains that we are currently and we'll be studying and you can see here some of the areas of interest, including health care utilization with different CAR T cell products, including ALL B-cell, correlative analyses using samples to try to understand T cell phenotypes and persistence. And a whole array of, I think, really interesting and important questions that we can answer through this elaboration. With that, I'd like to turn this over to Dr. Gabor.

Thank you very much, Dr. Motley, and good afternoon, everybody. I'm so fortunate to be here today. To be part of this journey where we will cure cancer with...

Ladies and gentlemen, please stand by. We're having some audio tech difficulties. Please stand by. We're having to audio technical difficulties. Please stand by. Dr. Jabbour, please continue.

Very sorry for this technical call issues. So I was saying I'm very fortunate to be part of a journey where we will cure ALL. And curing ALL is not only by giving therapy for a lifetime of 3 years. We have a unique opportunity today to ALL with immunotherapy and ALL B-cell as a frontline consolidation. And the reason -- next slide, why, the reason why I'm so confident in what is the rationale behind it. What we know and what over from my colleagues that ALL B-cell and CAR T in general work better in somebody will go to [indiscernible]. It means if you have a minimal disease or even less, you can have a better outcome that has been shown in the FELIX. And what we know today with our front-line therapy, we're reducing the high MRD negativity remission by NGS up 70%. Furthermore, when you get somebody in the frontline, the T cell are with it. So when you get CAR T in a multiple lapssetting, you're going to have a T cell at best, they don't have a great fitness. So here, we have fit sales where we collect them at the beginning. And finally, CD19 expressed on all these patients. there's no short of date for expression. So we have a full target express. We have a low tumor burden. We have very fit T cells. And therefore, I think it's a major opportunity today to consider collection retail at the beginning and give visas a consolidation. We published back in 2025 in multiple reviews highlighting our hypothesis and where we're going. In Houston, we pioneered the work of blinatumomab in the frontline. We were the first to have a trial with a blinatumomab in a Ph-negative and [indiscernible]. And we've shown that the integration of hemotherapyfront can deepen the response and improve survival. The next question is, we get therapy for lifetime, we give [indiscernible] by adding CAR T cell upfront, can we further deeper respond and pay for transplant? And second, can we shorten the shipment duration from 3 years to 6 to 7 months or 1 year. And now in USA, a lot of patients cannot complete the therapy because it required a lot of time and investment. So if we can offer something quite effective in using the deep sense remission, then we can change the outcome for all our patients in USA today and hopefully worldwide. Next slide, please. So how the fourth line landscape is changing? How has been redefined today? What we know for 30 years, we used chemotherapy and we had a [indiscernible] in Houston, and we had a 5-year survival at 40% altogether. Of course, other patients did worse. The revolution came when we had a TKI for PSL and then the immune therapy. And we designed in 2016, the blinatumomab [indiscernible] strategy in PH1 LM that was transformative to alleviate in for chemotherapy. So we had chemotherapy and onetime direct tax bank. And I perceive that -- but then we added -- we moved to purely immune therapy upfront in Phil, where we have [indiscernible] a survey of [indiscernible] and then in a negative we pin the work with the blinatumomab and inotuzumab combination, we improved the survival to 80%, 90%. But then there's still work to do. And that is where in 2025, in 2024 to go back with the collaboration with Hotels, where we designed the first [indiscernible] the frontline. The idea is we take [indiscernible] patients where transplant is offered and we will replace [indiscernible] with the CAR T cells and the vast majority of our patients who are defined by high risk, MRD positive and also a chart. Now what we know and why ALL B-cell? We picked ALL B-cell because it worked so well in minimal disease. It will be a great continuous to our fraud line strategy. In the frontline, you cannot afford to have any safety concerns. ALL B-cell has the lowest rate of adverse effect Grade III and IV. ICANS [indiscernible] ideal for the frontline combat. We know furthermore, that [indiscernible] care lead -- but when you feel the cells are for assistance, we have the [ 4-1BB ]continue domain, and therefore, that will access to raise. And today, if we design also based on MRD, MRD has become an integral part of our management of ALL and it's recommended by every societies where we must save our turbine on MRD and therefore, CAR-T will be great at. And post CAR Ts, we can measure MRD and persistence and make a decision whether to pursue treatment or not. Next slide, please. So I mentioned why ALL B-cell? Because of the mega of action being put off, leading to less toxicities and less Grade III and IV ICANS and [indiscernible] we've seen obviously quite effective in astatisetting with a 77% point rate. We've seen, and I reported at ASH that to lose high MRD activities and has to respond, they can become MRD-negative if they have a lots of relapse and the outcome is highly predictable. We've seen as well from the obvious experience that when you get the office, you have [indiscernible] and this sells assets surveillance towards anatomic also present and therefore, having somebody having NGS [indiscernible] and having persistence, you can predict the greatest outcome at a long run where you have a plateau for survival and the manufacturing has been very reliable. And furthermore, in a frontline setting we collect on the [indiscernible] I scheduled my infusion, therefore, it's selective. And therefore, win-to-win time is very manageable, very short and that is not an issue. For this reason, we select ALL B-cell as our partner to be used as a consolidation in a frontline setting. Next slide, please. Now who are these patients who may be from this approach? Ideally, I'd like to give everybody of ALL B-cell in the front line. Every patient gets [indiscernible] front line and move their out. We started by selecting patients at high risk PH-like 2-post came to DC, mutation, compress [ hypodeployde ]. We know these patients have a tip outcome and require a transplant and even with the transfer, they do not do so well. We know that blinatumomab may not work so well on [ hypoleployee ], and we believe CAR-T can have -- beat independent reaction can offer arenifor these patients at high risk -- we will take patients or MRD-positive, we know this who has a [indiscernible], MRD positive, they have persistent disease. And we know, obviously, we'll offer the optimal approach for these patients with minimal disease to inflate outcome. We will take patients who are [indiscernible] for transplant because of the nature of the disease, all the people are not brand candidate. And finally, I get so often patients coming to Houston. They will tell me after I've seen so and so in the ore transplant. I'm coming to CE because you have trust where you can spare me the transplant. And I said, okay, great. And as [indiscernible], who came to me just because they don't want to get transplant elsewhere and want to get something else, and we offer them obviously, consolidation when we measure MRD post-[indiscernible] and negative and persistent than the deal return. So here the scheme of a trial where we get everybody getting immunotherapy-based regimen upfront being high perceived or municipally depends on the age of the patient with Inogen. We assess them after cycle 1 and cycle 2 and we have two risk factors, dynamic based on MRD and static based on biology. We will collect patient after second one. We engineer themselves and we continue our bridging therapy or our chemotherapy plant. The cells already we infuse the cells. We measure post-[indiscernible] and MRD negativity. If patient is persistent and then payments over. It's done. We cut our fingers for a cure. It's not that we consider strategy to escalate among the stem cell transplantation. We believe this will be transformative and will shorten therapy all from 3 years to 6, 7 months. If we're successful here with we hope we will the and so far, we opened the study in December of this year and with [indiscernible] patients so far, and of course, too early to tell, but I can tell you excitement and the results are so far promising but still too early -- I believe this will be transformative and will change the way which added forever. Next, please. So we went from a date disease in ALH positives and same for PHM to a curative disease. We went from cure rate of 10% in a PH positive to 90% today, and the PH negative from 40% to 89%. Yes, we rely on immune therapy and transplant. And today, we have the opportunity to our the next chapter by offering ALL B-cell frontline to our payment and cure ALL with 6 and 7 methotherapy and main treatment they pass for all areas diagnosed in the U.S. in a world. So the biology favors CAR T. [indiscernible] is its product and the best because of the upfront because of safety because of the persistence of action. And finally, this will be an unmet need that will fill the need of patients were wide with ALL. With that, that's all what I have to share with you today, and I'll next pass it back on to Dr. [ Potier ] to go this presentation.

Thank you. It's a great opportunity to be able to share the pediatric perspective of this data with you. Hopefully, you all hear me well. If you could advance to the next slide. What I'd like to do today is share with you a few things. One thing that's important to understand is that CAR T cells targeted acetate are really a mainstay the approval for children occurred in 2017 with a different product, and it has come to be something that we are using very significantly. And we're very excited to get ALL B-cell on board. We have a number of research gaps and challenges that I'm going to briefly review with you. And then what I'd like to do is to share some of the early results of the catalyst Phase Ib which is the first experience of this specific product in children. And then finally finish by talking about our plans moving forward in order to get regulatory approval. Next slide, please. So currently, CAR T cells really are used extensively in children, but mainly used in children who have refractory or relapsed disease. As I mentioned earlier, the original approval of [indiscernible] occurred in 2017, and this was the first approval actually in -- and it was done in children before adults. This particular approval has, over the years, been refined and what we've learned with using a 4-1BB based CAR T cell targeted at CD19 for pediatric ALL is that we can have better outcomes when we use low burden and use it earlier in the disease course. The use has increased every single year over the last several years. The last data that we -- a year that I have data from is 2022. And -- but thing that's occurred over that time period is an interesting shift more toward earlier phase patients, it used to be patients who had relapsed multiple times. And almost 70% of the initial patients who were treated at relapsed after transplant. And now it's being used much more for primary refractory or secondary refractory patients. The other thing that has come up as an issue is trying to understand exactly when CAR T cells should be followed by transplant in children in order to maximize outcome. And we've developed a few assays that may give us some insight to really understand who can be rescued just with CAR T cells and who may want to be able to -- who may need additional therapy. But one key thing to understand about all of this is that these very high-risk patients who initially had a survival of less than 10%. Now have an overall survival. Greater than 5 years that is greater than 60%. Next slide, please. There are a number of research questions that we need to understand better. In children, adolescents and young adults, and some of those are going to be addressed with the ALL B-cell trial. The first is that we know that early first relapse of ALL in children have dismal outcomes. In children, the landscape is a little bit different. We can procure a lot of patients with chemotherapy. And although we're all working hard to try to move CAR T cells into a very upfront therapy, we have such good outcomes that were not able to approach it yet. What we're trying to do though is get CAR T cells to be used at first relapse. And we know that almost all patients who relapse end up having very poor outcomes. So our hope and goal is to move it into first relapse. We also know that MRD level after consolidation when patients are initially treated means that they generally need to move to transplantation. And our hope is to use CAR T cells instead in that population in order to avoid transplantation and improve outcomes. We also have a wide variety. Dr. Motley showed a really nice example of a woman with down syndrome. We have many special populations that really need CAR T cell early into, including down syndrome frail patients who have multiple complications of chemotherapy, organ damage and infection. Specific [indiscernible] subtypes that Dr. [ Debora ] mentioned, they're highly susceptible to have complications and problems associated with intense therapy and infants who have very high-risk BALL and a very poor prognosis. Next slide, please. This has led -- these things are being partially addressed by some of the early studies with ALL B-cell. And I want to go over that with you briefly. Move to the next slide, please. This was presented at ASH this past year with a follow-up presentation at Tandem. And what this is essentially is a brief overview of the trial. This was a single-arm open label trial. All patients had to be true pediatric less than 18 years of months excuse me, less than 18 years old, and they had to be relapsed refractory. They were collected, given bridging therapy and treated as per standard CAR T procedures. Next, please. 23 patients received oversell at the tart dose. And all of their products were within specification with no manufacturing failures. And of the 23 patients who are treated, what you can see is they got various things to bridge them most with chemotherapy, some with immunotherapy as well. Next, please. Our safety as with the adults was really much, much better than we're used to with other card products with exceptionally low rates of Grade III or above CRS. In fact, we only had patients who experienced Grade III or above and one was a highly refractory, very challenging patient. We also had very little infection. In addition, much lower reduction rates than were used in these patients as well. Next slide. What you can see here Is new field recovery. And this is quite remarkable. Generally, having studied this extensively using other car products, a vast number of patients have significant neutropenia at day 28, which is then prolonged with 30% having at 3 months and up to 20% having prolonged neutropenia later. And as you can see here, we're getting much more rapid recovery of counts than what I would expect. Next, please. The efficacy is really outstanding with the 21 of 22 patients having a response achieving CR achieved in 20 of those patients. All responders were MRD negative. And these responses have continued. So again, a really excellent outcome. These are early results, but the outcome is outstanding, which has really set us up. Next, please, to move into the next phase. Now this final slide that I want to show you about this just shows pharmacokinetics and pharmacodynamics. And what we see here is persistence excellent expansion and persistence of this car for extended periods of time. Next, the conclusions I'll mention just briefly, and that is essentially a great safety profile, extremely high response rate. And while longer follow-up is needed, this really gave us encouragement to move forward with regulatory approval studies. Next, please. That leads into what's currently going on in order to get this product approved in children. Working carefully with the Children's Oncology Group, the initial group that did this study is bringing in several more centers, but we decided to do a joint study along with the Children's Oncology Group to have more rapid accrual. What you can see here is a little bit of background that focuses on that first relapse group that I mentioned to you. In a study 1331 that we performed in the [ Chilean ] College Group a short while ago. Patients were treated with induction followed by blinatumomab followed by transplantation. And what was noted was extremely high rates of toxicity and very poor outcomes in that 40% of patients didn't even go in ratio to go on to get blind or randomization and CMO study. And the overall intent to treat reps from the beginning of the study was only 25%. There are no current indications for CAR T cell therapy use in first relapse in children, and this is a really critical need. Next, please. Our planned expansion is, of course, working with the Children's Oncology Group and the centers that we're already participating in the Phase Ib and adding an additional 30 ALL patients for a total of 54 with at least 15 slots for high-risk first relapse. And the reason for that, of course, is we want to listed on the FDA indication that high-risk first relapse can be traded in this way. What you can see there is a number of secondary endpoints that we think are very important. Our study design is almost identical to the initial study with screening enrollment, bridging therapy is needed followed by lymphodepleting chemotherapy and infusion. The expansion, again, includes that first relapse, and this is bolded in the next slide where you can see our inclusion criteria. Primary refractory as defined as what you can see first relapse and then the higher-risk patients in second or greater relapse or relapsed after transplantation. Next please. These are some exclusions, which I won't dwell on. But essentially, we are treating almost all patients that we can with this group. The study was activated in the Children's Oncology Group. It's been activated and open and 3 patients have accrued so far on the Phase II portion of it -- the study is currently a primary children's in Newton, Motion San Antonio. And you can see 8 additional COGS sites that are in the process of opening it. So our hope, of course, is to move rapidly forward with this study. The next slide shows acknowledgment of a number of individuals who've helped develop this. And I want to just move to the next slide to open this up for any questions that the group would like to ask of our group.

Thank you, Dr. Pulsipher, and thank you to all of our speakers. We are happy to take questions via the webcast platform. I have a few queued up here so we can jump right in. First is, any comments on other forms of toxicity in the ROCCA study. This may be important given older patients being treated.

Thanks a lot, Amanda. I think, Lori, that would be clearly one for you. Obviously, you're focused on particularly the immunological toxicities with CRS and ICANS. But clearly, these patients do experience our adverse events. I think it would be great to get a perspective.

Yes. Thank you. We -- in our initial -- the data that were presented this past winter, we did not dive into other side effects very deeply such as infections. We did an analysis looking at recovery hematologic recovery and found overall, the rate of hematologic recovery really neared other CAR T cell therapies in this space. But I think as time goes on and our numbers grow as ALL B-cell becomes the sort of most -- the CAR T of choice in this country, I think we'll have an opportunity to delve a little bit deeper. I will tell you anecdotally, I think because of side effects, immunologic side effect profile is so favorable. We are seeing fewer and fewer infections and fewer related issues in the clinic.

Next question, is there any potential downside for long-term OB cell surveillance in patients getting frontline consolidation?

That's obviously a very interesting question. I think, [ Ali ], when you think about kind of the frontline treatment, obviously, these patients are very heavily treated today and they're monitored for long periods of time. How would you see kind of the inclusion of ALL B-cell sell into that upfront treatment, how that would impact in terms of the need for long-term follow-up and surveillance.

FELIX that earlier use of UBC has been associated with a better outcome. When it comes to MRD negativity sustained fitness less relapses. And that will translate into the front line as well, where you get somebody in a font line with a very fit cell. You gave them ALL B-cell early on with minimal disease or no disease, therefore, fitness is preserved. The cells are persistent and expanding, and we might buy NGS for MRD thereafter. The way I foresee the future is that instead of giving therapy for 3 or 4 years, in AML, we have an opportunity here to give therapy for 6 months, for example, [indiscernible] and [indiscernible] seller benefit for persistence energy cement activity and cure the disease. I don't see any downside of this, I think nothing but great outcome. Now of course, we need to have a long-term follow-up. And what you've seen so far from ALL B-cell 3 and 4 years of follow-up, there are no adverse events, nothing major, significant. The most adverse event were encountered the first month or two. And in fact, FELIX feel [indiscernible] there was no adverse events. We have to watch for infections, [indiscernible] and that is looking practice to give [indiscernible] if needed in [indiscernible], but nothing out of this work.

Next question for frontline consolidation, what would be considered positive in terms of MRD negative rate and durability of CR or MRD?

What we have so far when we gave blina upfront, our MRD negativity rate by NGS at 0% to minus 6 is around 70%, 75%. But here, there's one caveat that time to MRD matters too, we know that high risk do not get into MRD negativity at the beginning, and that is detrimental. And of course, they require transplantation. So we can improve on that because we know today from ALL B-cell given in a front line or our own reward data or from the FELIX that most of the patients can get into margin activity are on a month on post CAR T. So I think improvement MRD is feasible, it's granted. I think the point -- the second part of the question is how durable this will be -- so the primary of the study is relapse-free survival to see if we can really induce sustained MRD negativity rate that can trust it into cure. And today for the FDA, for example, such an MRD activity rate sustained can be sort of case for approval of new drugs. So so far, what you've seen when -- at from the field expectation who had left the treatment, low tumor burden, MD was highly applicable for a long-term outcome and therefore, peer durable. So we extrapolate from the FELIX salvage one, to the front line, if you get into 90% MRD activities higher at 1 month post office infusion this based on historical evidence should be sustained in the vast metro the patients. And of course, we more to them. Now in case of patients who do not achieve the response or any time with more like a conversion to positivity, we can go for transplantation -- but again, extrapolate from FELIX, that is very reassuring and that's what the hypothesis to go into the frontline.

Thank you very much. Any additional questions?

Yes, just a couple more questions. Can you remind us about the path to getting frontline consolidation onto the label and potential timing and next data presence.

Okay. Great question. This study is ISD and Dr. Park with me and mostly will have another study with [indiscernible] as well is ongoing. So we have a patient 30-patient study. And with the study, we can have good evidence to go into [ NCCN ] and make this product available to the old USA patients. Of course, that will not be worldwide available. And then the next step will be to discuss with the agency based on this evidence if we can run into a single-arm trial solid enough to get approval or randomize shell, but that has be discussed down the road once we get these studies conducted and completed. From my side in Houston, I think we can complete the study this year in 2026 and have a long-term follow-up for a year or 2, and then it should be part of SCN in 2027.

Thank you. ROCCA data looks pretty good, and we can see where there is evidence beyond FELIX. How has this changed the uptake of [ Ocata ] in your practice? Or how do you envision it changing your usage in the 2026 or 2027 time frame?

Christian, would you like me to take that?

Yes, please.

Sure. Yes. So I think that the -- that's a great question. I think that the ROCCA data as well as the lived experience of these now 50 centers that participate suggest that the transformation to using ALL B-cell as the best-in-class CAR T for adult ALL has already happened. We see the numbers increasing in our consortium. And our next data output will be at ASH this coming ASH, but I think the data, of course, help, but they're not surprising to those of us that use this product because it's just -- it's very, very easy to use. I agree with Dr. Jabbour said and I think that there is an enormous opportunity to move this into the front line and to move this into children. But really using ALL B-cell. And this is what I tell my team, which we are a large CAR T cell center, is that this is we really -- this is a CAR T, but you don't need to think about it like a CAR T. These patients can remain at home. They really do not require nearly the same amount of side effect management. So it's just a really nice smooth, easy therapy. And I think that the use -- the increase in use in this coming year will reflect the toxicity profile that we're seeing in the real world.

Final question here. Can you put into context the risks from transplant-related mortality compared to CAR T talk?

That may be a question for Jay.

Sure. The transplant-related mortality that typically in average, a national average has been about 20% to 25%, although the [indiscernible] and Comorbidities and type of a transplant and did status they do get, but that's the national statistics, some are a little bit lower in experience centers. the CAR T, the treatment-related mortality or those are extremely low for -- especially with an ALL B-cell because of the CRS and ICANS rate or the infectious complications, which are the predominant reasons that some of these patients die within a few weeks of receiving CAR T cell therapy. So I think the data from the FELIX study has been very encouraging with a very, very low rate. It's certainly much, much better than the transplant, which is exactly the reason why that we are excited about moving to frontline setting that we would not have done it, obviously, if the reason transplant-related or treatment-related mortality was very high. Thanks, Dr. Park. Christian, that concludes the questions. So happy to turn it back to you.

Very good. Thank you very much. I'm just going to wrap up briefly on Slide 47. Obviously, what we wanted to do with you today is look at what we've achieved so far with the product and the initial launch of the product. And I think the data coming from the ROCCA consortium was a real reality check for how the product actually performs and is frankly, giving us an opportunity to broaden the patient population that can actually be considered for CAR T therapy. Ongoing in terms of immediate next steps, obviously, the work that Michael Pulsifer was going through looking at the pediatric work that we've been doing, we have obviously good initial evidence for the activity is based on the data that we presented at ASH at the end of last year on the CATALYST PY1 study. We're now obviously enrolling the Phase II portion. We had very good momentum also over the last month in the study, and we think we're going to be able to drive this study with a good momentum. The idea here is really to get ALL B-cell to a place where it becomes a treatment for any relapsed/refractory patient across the entire range. And that is obviously what the medium term and the ongoing activity is. And then as we look forward, as you heard from Eli, but also to Jae Park and Lori [ Motley ] engaged with their study to look at the ability to consolidate patients in the frontline setting with the drive towards the definitive consolidation and ultimately an abbreviated treatment in that important pace group. Moving to Slide 48. This is just a brief summary on how [ Ocas ] and ALL B-cell actually have an ability to get activity across refractory first relapse on line plus relapse. Across the age groups based on the clinical work that we're doing currently in the [ pit ] and expanding with that the utility that we already have achieved on the adult side. Moving to Slide 49. This sort of tags on to what Eli was describing on the frontline approach. What we see in this data set is that really it's the older patients, the MRD positive patients, the patients with complex genetics tend to actually still after all the intensification of the front line therapy that we've seen over the last probably being 20 years, still actually have limited outcomes and there is a real opportunity to improve outcomes for those patients. The first step, as we go to the last slide, Slide 50 is really to obviously drive and generate initial data and collective experience through the ISTs. With that, I think we start to get a good understanding of the profile of the product in the frontline setting and then take it from there. And with certainly the aspirational goal to ultimately move the product fully into the frontline setting as well. With that, I'd like to wrap up here. I would like to thank our fantastic speakers, Dr. Jae Park, Dr. [ Lori Motley ], Dr. Eli Jabbour, and Dr. Michael Pulsipher for fantastic presentations. Thank you for sharing your insights with us. And we're looking forward to, obviously, continue the interaction with all of you and looking forward to making a real contribution here to moving the ALL field forward. Thank you very much.

Thank you. This concludes our conference. Thank you for participating, and you may now disconnect.