Autolus Therapeutics plc (AUTL) Earnings Call Transcript & Summary

Hello, ladies and gentlemen. I am pleased to welcome to the Autolus Therapeutics ASH 2021 Investor Conference Call. As a reminder, this conference call is being recorded. I would now like to turn the conference over to your host, Dr. Lucinda Crabtree, VP Business Strategy and Planning at Autolus. Please go ahead.

Thank you. Good morning or good afternoon, everyone, and thank you for joining us and taking part in today's call covering the data we have presented over the weekend at the American Society of Hematology or ASH Conference being held in Atlanta. I'm Lucinda Crabtree, VP Business Strategy and Planning, and I'm joined today by Dr. Christian Itin, our CEO; Dr. Edgar Braendle, our Chief Development Officer; Dr. Wolfram Brugger, our Chief -- our Head of Clinical Development; Dr. Martin Pule, our Chief Scientific Officer; and Andrew Oakley, our CFO. Before I pass you to Christian for his introduction and opening remarks, I'd like to remind you that during today's call, our discussion will contain forward-looking statements. All statements, other than statements of historical facts on this call, are forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the section titled Risk Factors in our annual report on Form 20-F filed with the Securities and Exchange Commission on March 4, 2021, which can be accessed on the EDGAR database at www.sec.gov and in subsequent filings we make with the SEC from time to time. The forward-looking statements on this call reflect the company's views as of today, December 13, 2021, regarding future events, and should not be relied upon as representing the speakers or the company's views as of any subsequent date. While the company may elect to update these forward-looking statements at some future point, the company specifically disclaims any obligation to do so even if the company's views change. These forward-looking statements should not be relied upon as representing the company's views as of any subsequent date to today. Please be advised that today's call is being recorded and webcast. So on Slide 3, you will see the agenda for today, and it is as follows: Christian will provide an introduction before passing to our Chief Development Officer, Dr. Edgar Braendle, to walk you through the obe-cel Adult ALL update; Dr. Wolfram Brugger, our Head of Clinical Development, will then run you through the obe-cel B-NHL data. And then Dr. Martin Pule, our Chief Scientific Officer, will talk about the AUTO1/22 data update. Finally, Christian will close with some summary remarks before heading to Q&A. So with that, let me pass you over to Christian.

Thank you, Lucy, and welcome, everybody, to our ASH update for ASH 2021. The focus of the ASH update that we've given during the course of the conference were in obe-cel and the next-generation program called AUTO1/22. As you remember, obe-cel has a unique design of mechanism of action, and we believe actually has the potential to be a best-in-class CD19 CAR program, and we'll obviously provide data now both for adult ALL as well as for non-Hodgkin's indications as part of the presentation today. A key update that we provided was certainly the longer follow-up on the event-free survival in the ALLCAR19 study. We have now 29.3 months of median follow-up in our patients and that gives us a very good view on the overall durability of the effect. So the morphological entry survival that we see with ALLCAR19 in these adult ALL patients is that we see the event-free survival stabilize at around 12 months. And then actually, as we get out to 24 months now reaching 46% event-free at the 2-year mark. We also provided an update on the initial portion of the FELIX study. Remember, the FELIX study is designed as a Phase Ib/II trial what we're providing the update for is the 1b portion of that trial. And we're obviously looking at the outcome that we've seen in the trial and compare it to the experience that we had in the ALLCAR19 study, all of those obviously addressing adult patients with ALL. We're very pleased to say that we see a very consistent data set across both trials. We do see an excellent safety profile with none of the patients experiencing high-grade CRS and only very limited neurotoxicity. And we also see a high level of clinical activity in both [ beta ] trials. What is certainly one of the hallmarks of the obe-cel program is the exceptional persistence that we're seeing in the program, which obviously matches the profile that we're seeing on event-free survival and have this ability to put continued pressure on the leukemia over time. In addition to focusing on our work that we're doing in ALL and in -- particularly in adult ALL, we also obviously are exploring the activity of the program in non-Hodgkin's lymphoma patients, and we'll provide an update on that as well. I think key take-home message is really that the program is very active. In non-Hodgkin's lymphoma, we have treated patients with follicular mantle cell and DLBCL and out of 13 patients treated and evaluable, we have 13 patients reaching metabolic complete remissions. We also started to treat CLL patients. And when we look across the entirety of the experience to date, again, we have a very good overall safety profile. None of the patients experienced neurotoxicity and none of the patients experienced high-grade cytokine release syndrome. Now the third part of the outlook that we're providing is on the AUTO1/22 program. This is, in essence, building on obe-cel and adding a highly potent CD22 CAR to the program as a way to minimize the relapses driven due to antigen or driven by antigen loss of the CD19 target that we're using predominantly with obe-cel -- also using with obe-cel on leukemic and lymphoma cells. This program is being evaluated in a pediatric setting, and Martin will give an update on the program as we go through the presentation. So we're now moving to Slide #6. We believe that we have now built a solid foundation for our business, really grounded in the unique profile that obe-cel displays with its unique mechanism of action of being a fast off-rate chimeric antigen receptor that we're using that gives us an ability to drive very high clinical activity, combined with long-term persistence and without triggering severe immunotoxicity. What is very encouraging is the consistency of the activity that we see across all of the trials that we have conducted so far with obe-cel starting with the original experience in pediatric patients, the CARPALL study then the first experience in -- with patients with adult ALL, the ALLCAR study and now the first portion of the FELIX study. We also obviously had an opportunity to update you as we went through the course of this year also with a pretty huge publications around the program as well. The -- in addition to, obviously, the consistency of the data that we have seen, we also, obviously, have made progress with regards to the regulatory interactions and have access to the accelerated review paths in Europe and the U.K. called PRIME and ILAP, and obviously are building also in -- towards that type of an approach in the U.S. When we look overall in terms of the key outcomes and focus for the 2022, it's clearly the conduct and the outcome of the pivotal study that we're conducting, the FELIX study, the Phase II portion of it, which will drive key news flow as we go through the course of the year and also the fundamental value generation that we're looking to achieve with the program. Now we're expanding, obviously, into non-Hodgkin's indications and exploring the activity of the next-generation program, AUTO1/22 as part of life cycle management and the approach in pediatric ALL as we go through the course of next year. And we'll expect from all of those activities and actually data to be presented in 2022. Finally, we've been able to, obviously, support the overall program towards commercialization through the funding support from Blackstone $250 million commitment towards the obe-cel franchise and the ability to, obviously, drive that program towards commercialization. And we're also in the process of building up our manufacturing facility for commercial supply in -- also in the U.K., which is a 70,000 square feet -- square-foot facility that we expect to get online in the next 12 months. So with that, I'd like to move to Slide 7, and this is just a brief view on the clinical trial activities that are ongoing. As I indicated, we expect to see data presented during the course of next year, updates from all the trials. Obviously, the FELIX study, fundamental, obviously, value step in terms of driving towards to pivotal data in the adult ALL setting, the extension of the ALLCAR19 study and filling out the cohorts in non-Hodgkin's lymphoma in CLL patients, including, obviously, follow-up on these patients, exploratory clinical trial in patients with primary CNS lymphoma called the CAROUSEL study, and then finally, the extension of the CARPALL study for AUTO1/22 in pediatric patients. So with that, I'd like to actually hand over to Edgar, who will introduce you to the ALL program and the experience in the early part of the FELIX study. Edgar?

Thank you very much, Christian. Good morning and good afternoon to everyone. Julie, if you can move to Slide #9. What I would like to do in the next few minutes is to provide you an update and overview about our obe-cel program in relapsed and refractory adult ALL. Before going into details in both of these studies I will talk with you about, I would like to shortly touch on the high unmet medical need in relapsed/refractory adult ALL. Despite the fact that the newly diagnosed adult ALL with a combined chemotherapy has a high response rate. There are still 40% to 50% of patients who will relapse and will be relapsed and refractory at this stage. And those patients will have a dismal diagnosis. And the medium overall survival is less than 1 year in those patients or to put it in other terms, the 1-year overall survival rate is about 26%. Despite the fact that the potential only curative treatment which those patients have a transplantation, we have to be mindful that, number one, not every bedded patient is eligible for transplantation, and transplantation is still associated with a significant mortality and morbidity. So there's a still high unmet medical need in relapsed/refractory adult ALL setting. And at this stage, there are 3 therapies approved for relapsed and refractory adult ALL. So Julie, if you go to the next slide. This slide basically provides you to -- Slide #10 provides an overview about those products, which are currently approved in the relapsed and refractory adult ALL setting. And you see, on the one hand, it's blinatumomab, which is a monoclonal antibody bispecific T cell engager targeting CD19 and CD3. Then there is inotuzumab, which is an antibody conjugate against CD22. And recently in the United States approved a Tecartus based on the ZUMA-3 study. I will go very shortly to the data, which, to some extent, also confirms a high medical need in this setting. So if you look first to Inotuzumab and blinatumomab, you see that the overall response rate is between 44% for blinatumomab and to 80% for Inotuzumab. But I think the important point here is that the medium duration of response is quite short, and you see that for blinatumomab is about 7.3 months and for inotuzumab 5.4 months. In addition to that, there are toxicity associated with that, you see for blinatumomab, CRS Grade 3 and higher about 3% neurotoxicity Grade 3 and high about 13%. And you see that the main toxicity associated with one of the major toxicity is in the -- 14% is hepatic veno-occlusive disease. And specifically because of the short duration of response, many patients are transferred to transplantation. You see that in both cases, blinatumomab as well as inotuzumab, 50% of patients go to transplantation. So both of these treatments are used as bridging. Now let me shift a little bit to ZUMA-3 Tecartus which was recently approved in the United States for adult relapsed and refractory ALL. And you see the response rate is 65%. The medium duration of response is 13.6 months. But you see there are some significant toxicity associated with that Grade 3 CRS and higher about 24%. Neurotoxicity Grade 3 and higher about 35%. And what we know is that about 50% of all patient in the ZUMA-3 study was admitted to the ICU. So if you can go to Slide #11, this basically shows you the trial design of both studies we have conducted with obe-cel in the clinical setting of relapsed and refractory adult ALL. And the first study we conducted is the ALLCAR19 study. This was done or driven performed with our academic collaboration with the University College of London. This was an academic study. And later, based on the very encouraging results we have seen, we started a company's sponsored program, which is a FELIX program. And the FELIX study basically has 2 parts. One is a Phase Ib part and then it has a Phase II part. And the data I will update you on today is basically on the FELIX Part 1 as well the ALLCAR19 data. The trial design for both the ALLCAR19 data as well for the FELIX study is the same, which is depicted here on the slide. I would like to only draw your attention to one thing. We are using the split dose of obe-cel in both studies. And so depending on the disease burden, we give different doses. And you see at the blast count if the disease burden is low -- below 20% of blast count, it's screening, a day 1 patient received 100 million. And then on day 10, 300 million cells -- 310 million cells. And if we have a high disease burden, on day 1, patients received 10 million cells and the second dose, about 400 million cells. One additional difference between the ALLCAR19 study as well the FELIX study is the initial manufacturing process we use for the ALLCAR19 data was an academic manufacturing process, and we have produced -- now put it in-house and have industrialized the manufacturing process. And number one, to fulfill the regulatory requirements but also to support the commercialization. And one of the differences we have in this product is that we now are also in a value position to handle leukapheresis product with a high leukemic blast count. If you move to the next slide, this is basically comparing the patient correctors between the ALLCAR19 study as well the FELIX Phase Ib study phase. And you see basically that both of the patient characteristics are quite matching. You see all of these patients are heavily pretreated. You see the median prior lines of therapy is 3. You see that many patients have been treated previously with Blincyto and Inotuzumab. 50% of all patients in both studies had prior transplantation. There are some minor differences. We see that in the FELIX study Phase Ib, they are more treated with Blincyto priorly. And we also see that the patient, which have been enrolled in the FELIX study Phase Ib, had high disease burden, the medium blast in the ALLCAR19 study at screening was about 43%, in the FELIX study Phase Ib, 75%. If you move to the next slide, which is Slide #13, this shows you a comparison between the efficacy and safety of ALLCAR19 and the FELIX study Phase Ib. You see that in the ALLCAR19 study, the overall response rate was about 85%; and the FELIX study Phase Ib, it was about 75%. But please keep in mind the number of patients are relatively low. We had 20 patients in the ALLCAR19 study and 16 patients in the FELIX Phase Ib study. If you look to the safety profile in both studies, obe-cel was very well-tolerated. And you see CRS any grade in the ALLCAR19 study about 55%; and the FELIX study Phase Ib about 56%, very comparable. If you look to Grade 3 CRS and higher, we did not observe any Grade 3 or higher in both studies. If you look to the neurotoxicity to the ICANS, any grade of ICANS in the ALLCAR19 study, 20%; and the FELIX study, Phase Ib, 13%. And if you look to Grade 3 ICANS, there were about 15% in the ALLCAR19 study; and in a FELIX study Phase Ib about 6%. If you compare this to the results of ZUMA-3, the CRS Grade 3 in the ZUMA-3 study was about 24%; and the ICANS, Grade 3 and higher were 35%. Now on the right part of the slide, you see the CAR cell -- CAR T cell persistence. And you compare -- we're comparing against the ALLCAR19 study. And as a measure for the comparability, we're using Cmax here. And you see that in both studies, Cmax data are quite comparable. The same is true for the AUC data. If you go to Slide #14. This basically gives you an update about the durability of response we have seen in the ALLCAR19 study. So on the left side of the slide, you see the persistence of the CAR T cells. And you see, as it has been shown in the publication in JCAR in August of this year. Basically, a long persistence of the CAR T cells. You see it's going up to 24 months in this publication. And this long durability of persistence of the CAR T cells translate in the long durability of response. And you see here for the long durability of response, you see the Kaplan-Meier curve on the right side of the slide. And you see that the Kaplan-Meier curve for the event-free survival dropped -- stabilize at 12 months, and then it's stable up to 30 months. So it's a very long durability of response. So if you move to the next slide, which is Slide #15. I think what we have seen here is a very consistent results between the ALLCAR19 study as well the FELIX study Phase Ib, the Phase Ib part of the study in both safety as well in efficacy. And what we see here is basically that obe-cel has the potential to become the best-in-class product. This is, number one, driven by the efficacy. We see high response rate between 75% and 85%. We see a long durability of response based on the ALLCAR19 study with EFS data around 46% at 24 months and beyond, and we see an excellent safety profile with no Grade 3 risk and with a very low number of Grade 3 ICANS. We also see in the ALLCAR19 a long position, which is driving the long durability of response. And as Christian already pointed out, we are now in the Phase II part of the FELIX study, which is our pivotal program. And the study is currently actively enrolling patients. and we will report about the data of the FELIX study, the Phase II part, by mid of 2022. As Christian also pointed out, we have engaged in regulatory interaction. We received the ILAP designation in the U.K. from MHI as well a PRIME designation in DAU. With that, I will hand over to Wolfram to speak about the program in non-Hodgkin lymphoma as well as CLL.

Thank you, Edgar. Good afternoon, good morning, everyone. So in the lymphoma program, this is part of the ALLCAR19 study. These are extension studies. And in contrast to the ALL cohort in the lymphoma program, AUTO1, obe-cel will be given as a single dose indicated on the slide at a fixed dose of 200 million cells given on day 0. In the DLBCL patients, in addition to the standard Flu/Cy lymphodepletion program, patients will also be treated or are being treated with 1 single dose of pembrolizumab in order to deepen the persistence and the engraftment of the CAR T cells. In the B-CLL and small lymphocytic lymphoma, cohort patients, again, will receive a split dose regimen at a dose of 30 million on day 0 and 200 million at day 9 to mitigate the risk for severe CRS or ICANS. If we go to the next slide, please, Slide #18. This shows the B-NHL and the CLL cohorts, the patient disposition on the left and the baseline characteristics on the right. We have treated so far, in this ongoing study, 16 patients with AUTO1. As you can see on the right-hand side, the median age is roughly 60 years, it's more or less consistent with what is standard population in this relapsed/refractory setting, we have treated 7 patients with follicular lymphoma; 4 patients with diffused large B-cell lymphoma, including a couple of patients with transformed follicular lymphoma; and 3 patients had mantle cell lymphoma. Currently, 2 patients with CLL with relapsed/refractory CLL were dosed with AUTO1. The median number of prior lines of treatment were 3 with a range of 2 to 5 and almost all patients received a bridging therapy, the lymphoma patients, mostly chemoimmunotherapy regimen and 1 patient only received rituximab, which is an immunotherapy only. If we go to the next slide, please, Slide #19. You can see the favorable tolerability profile of obe-cel in the lymphoma patients, which is consistent with what we have seen also in the B-ALL cohort. So there were no ICANS and no severe CRS syndromes in any of these patients. So really consistent with what we have seen before, and more importantly, no new safety signals were upset. If we go to the next slide, #20. This shows the excellent T cell expansion and engraftment in this lymphoma patients in the B-NHL patients up to 9 months. And the Cmax is pretty high, as you can see on the right-hand side of the table. If we go to Slide #21. This shows the encouraging efficacy and the duration of response in these non-Hodgkin's lymphoma patients and the 2 patients with CLL. On the left-hand side, you can see in the swim plot, the 7 patients with follicular lymphoma, all of them received -- achieved a complete response, complete metabolic response. And you see the 3 patients with mantle cell lymphoma above the FL patients. There was one patient who had a CD19 positive relapse at 6 months but the other patients are ongoing. And again, as the best response, all of the 3 patients had a complete metabolic response. Likewise, the patients with diffused large B-cell lymphoma or transformed follicular lymphoma, they also had a complete metabolic response. And one patient is still pending. This is indicated with the gray bar, as you can see on the slide. And also there was one patient where the disease assessment is not reached because it's simply too early and the other patient with CLL in blue and the blue bar has achieved a partial response with a bone marrow being MRD negative. The median follow-up, you can see it on the right part of the slide on the bottom. The median follow-up time is slightly different for the follicular lymphoma patients in the DLBCL patients is roughly 12 months with a broad range from 2 to 14 months, and for the MCL cohort is about 7 months with a range of 1 to 15 months. If we go to the next slide, please, #22. So in summary, obe-cel cell has a favorable safety profile with no ICANS or severe Grade 3 CRS events, very consistent with what we have seen in the B-ALL cohort. Out of the 14 patients, which -- who are evaluable for efficacy, the response rate is 100%, and the overall metabolic complete response rate is 93%, 13 of the evaluable 14 patients. We have seen long-term persistence of obe-cel demonstrated by qPCR and 15 of 16 patients are ongoing without disease progression. 6 of the 7 patients in CR have a duration for more than 10 months. And 1 patient, as I mentioned, died in complete remission from COVID. Longer follow-up and additional patients will be included in this study. With this, I hand over to Dr. Martin Pule.

Thank you, Wolfram, and hello, everybody. If we can move to Slide 24, please. So many of you will know that we tested obe-cel previously in children with relapsed/refractory B-ALL. We published this data ingression at our Nature Medicine in 2019. And what we found in this study is that obe-cel in this setting had the same nice properties of low toxicity and excellence engraftment. However, children tolerate immunotoxicity much better than adults. And what we also found in line with the literature in pediatric ALL is that a major cause of treatment failure in this setting is CD19 negative escape. To solve this problem, what we need to do is to target 2 antigens simultaneously and the second antigen that is most logical to target is another b-lineage antigen, which is CD22. And I've shown in this slide, a cartoon of CD19 next to CD22, to remind you that CD22 is very challenging to target for a number of reasons. First of all, it's a very bulky, heavily glycosylated molecule and that makes formation of an immunological sign-ups difficult. Secondly, it's normally expressed at a log lower than CD19, and furthermore, after challenge with CD22, it down regulates even further to less than 1,000 copies per cell. So we go to the next slide, Slide 25. And we invested quite a bit of time developing a CD22 CAR that was sensitive to very low-density CD22. And this slide just shows you a quick illustration that on the left, it's actually quite easy to make a CD22 CAR against high CD22 expressing targets but it is actually quite difficult to make a CAR functions well against low-density targets. Here, we have target cells that express around 250 copies of CD22 per cell. We have a candidate 9A8, which shows excellent killing in response to low-density targets, but also excellent release of IL-2 in T cell proliferation in response again to low-density CD22 targets. So we move on then to Slide 26, how do we co-target both CD19 and CD22. As you will have heard, we're very happy with how obe-cel performs. And the option we've gone for is double the transduction. And what this simply means is during the manufacturing process rather than just adding 1 vector, which encodes for the CD19 CAR for obe-cel, we have 2 vectors: one, which includes obe-cel and one which encodes a 9A8 to CD22 recognizing CAR. The nice thing about this is that we don't have to touch obe-cel at all. We don't have to alter either the chimeric antigen receptor itself or the way the vector works. So we don't have to change how -- what functions and how it's expressed. The other interesting thing about this approach is that actually we get a complex CAR-T product at the end that has 4 populations. The non-transduced cells, double transduced and single transduced. And this is actually quite nice in a way because we can study the relative engraftment of the different subpopulations of CAR T cells in patients. If any of you have seen our poster, you'll see we've tested this extensively in vitro and in vivo. Here's just a little reminder of some of the data, on the top is a stress model of B-ALL using Nalm-6 cells. And you can see that AUTO1/22, the co-transduced products and performs well in this setting, perhaps even better than obe-cel alone. And below, we're showing a model of CD19 negative escape where CD19 is knocked out from the Nalm-6 cells. And there, you can see as expected obe-cel doesn't work at all because there's no CD19, but AUTO1/22 clear as a tumor very nicely. We started testing this in patients. And what I'm showing here is 6 facts plots, the day 28 from the 6 patients that we've treated so far and with this product. And this facts plot shows staining for the anti-CD22 CAR on the X-axis and anti-CD19 CAR on the Y-axis. Slide 28, sorry, if you haven't moved along with me. And here, you can see very nice engraftment of all the different subpopulations of CAR T cells and -- in all of these patients at day 28. So in summary, AUTO1/22 builds on the excellence of CD19 targeting with obe-cel by adding co-targeting of CD22 without making major changes in the way the CD19 part of this therapeutic works. We know that this product eliminates targets that express very low density of CD22 molecules and is highly effective in an in vivo model of CD19 negative escape. The 6 patients we've treated -- that we've dosed 6 patients so far and all show engraftment of both single and double CAR T cell population by flow cytometry. And with that brief summary, I'll hand back to Christian. Thank you very much.

Thanks, Martin. And we're moving to Slide 31. Obviously, as we've gone through the clinical data and updates now, I think it's very clear that we're having a very consistent picture with regards to the properties of obe-cel, which, as you remember, built on a very unique mechanism of action. It's a product that has a so-called fast off kinetic, from the target CD19 target on the leukemic or lymphoma cells. And that gives us a transit interaction, gives us a high level of activity without overactivating the CAR T cell. And with that, obviously, have the benefit of a much better safety profile, which you've seen at display across the various indications that we reported on today, but also actually gives us a product that can expand more. This is what we've seen in the update of the ALLCAR study, where you see that, in fact, at the peak, we're at about 10x the number of CAR T cells that we actually see in our patients compared with any other competitive products in the space. But it also then actually allows us a much better persistence over time. And obviously, finally, also by avoiding this high degree of overactivation, we also do avoid exhaustion of the CAR T cells and overall have a much healthier product. Now that translates, obviously, an interesting set of activities. You've seen from EDGAR the updated event-free survival data, where we see a stabilization of event-free survival at 12 months, and we can now see at 24 and 30 months that we're still at the same level of 46% event-free survival. There's no other therapy that actually today has been able to demonstrate that in adult patients with ALL. All the data sets that we've seen of any of the other programs actually continuously drops over time, and we don't see a stabilization. So that's very unique to the program, and it's one of the reasons why we're so excited about it. Now in terms of where we are with our pivotal program, we reported the first portion, the Phase Ib portion of the FELIX study, and that was really to actually demonstrate that indeed industrializing the process, moving the product into a multicenter international environment, we can actually demonstrate same level of activity and safety profile as we've seen in the ALLCAR study. And we're building, obviously, on that as we are now are active in the Phase II portion of the study with data planned, as Edgar pointed out, during the course of next year. Finally, on the expansion of the program into non-Hodgkin's lymphoma. I think it's remarkable that we're seeing 100% metabolic complete remissions in non-Hodgkin's indications, we see -- start to see activity in CLL, obviously, more data to be generated in those indications. And as we're going through the course of next year, we have an ability to actually get a better sense for the durability of those effects, and with that, start to get a good understanding of the program. The fact that we're seeing in follicular lymphoma with patients to be at around 10 months of observation, all patients being in continued remission is, obviously, very encouraging, and I think will point to kind of an attractive opportunity downstream, the ALL activities that we currently have ongoing. And as Martin pointed out, we're obviously building on the life cycle management around AUTO1/22, which builds an obe-cel as obe-cel is currently and adds on a highly potent CD22 CAR in that program. And we'll have data as we go through the course of next year that within our follow-up to understand where we actually can counteract what we had have seen with obe-cel in pediatric patients, which was relapses due to loss of antigen. And that's, obviously, what we want to see and what we want to counteract with the design of the AUTO1/22 program. Now with that, obviously, on Slide 32, again, a quick summary of the various studies and data sets. So we expect data from all of those studies updates as we go through the course of next year with, obviously, the primary focus being on the pivotal data set from the FELIX study in relapsed/refractory adult ALL patients. So with that, I think we're at the end of our presentation today. And what we'd like to do is actually open up for question and answers. And I'd like to ask the operator to initiate the Q&A. Thank you.

[Operator Instructions] Your first question comes from the line of Gil Blum from Needham & Company.

Maybe kind of broader organizational points. So was the lead-in portion in FELIX requested by a regulatory agency? Or was this always part of the plan to show comparability before moving on to Phase II.

Well, thanks for joining, Gil. Well, the Phase Ib was planned from the get-go. And the reason for that is as we moved into the company program, we're obviously transferring the manufacturing process. As Edgar pointed out, we made -- adapted the process to handle leukapheresis from patients that have a lot of circulating leukemic cells, which obviously means that also the cells you collect from the patient contains a lot of leukemic cells, and you need to adapt the process to get rid of those. So that's one thing we did adapt. And secondly, we also, obviously, switched to a commercial vector that we can use then also all the way through to the market. So there's significant changes that we made to the overall manufacturing process in terms of the specifics of the process. And that also, obviously, required us to do running into the pivotal study where we first actually demonstrate the comparability of the program and then actually transition from there into the Phase II portion.

Okay. I would also like to confirm that there were no production failures reported.

That is correct. It's one of the things we haven't discussed in the presentation. But obviously, the reliability of the manufacturing process is incredibly important, and we're very pleased to say that indeed, we're able to manufacture all patients.

Okay. So maybe moving to the indolent lymphoma, some very impressive data coming out from this product. Do you think the emerging safety profile will overall be differentiating specifically in indolent lymphomas, considering there are other seller therapeutics coming out with good data in indolent lymphomas?

I think the way I would think about this is that the safety profile -- a good safety profile is a prerequisite to be able to position your product in indolent lymphoma. Because obviously, a lot of the other treatment options are given in outpatient setting, et cetera. So you need a very good overall safety profile. But the other thing that I think is important to note as well is we heard that through the conference as well in various presentations is that the ability to actually induce a true long-term remission in this patient group is very attractive. And there's frankly no other therapeutic modality that gives you true long-term remissions in indolent lymphoma. And I think what we're starting to see is a very attractive, very unique type of profile. Remember, this is a onetime intervention that so far we collect in data from, which is very different from the continued need for therapy week after week that you basically go through as a typical follicular lymphoma patient where you get treated until relapse with the current regimens. So we believe this is going to become an attractive space, contrary to what probably a lot of people believe for a while back. But with the ongoing persistence and the ongoing of the clinical responses, we believe there is a very interesting opportunity slowly opening up here for CAR-T therapies in that space.

Great. And maybe one last one for Martin. Just something I saw at the poster. So any thoughts as to the higher activity that you're seeing preclinically with the AUTO1/22 versus AUTO1?

Well, maybe 2 cars are better than one.

Okay. All right. I think that's it for me.

Gil, what it speaks to -- sure. I mean, Gil, what it speaks to is the very high potency of the CD22 CAR that clearly seems to have a beneficial effect here. And one of the things that also I think we need to remember that certainly in vivo, we do have varying expression levels of CD19 and CD22. And to Martin's point, having 2 CARs in that situation actually gives you an advantage. So that's probably from a -- just think about it from a theoretical perspective, is certainly where you would think the edge would come from.

I'll stick with 2 is better than one.

Your next question comes from the line of Nick Abbott from Wells Fargo.

Christian, so with the FELIX data mid-'22, can you update us on where you are in enrollment for the pivotal cohort and also what we should expect in terms of follow-up at that first data announcement?

Yes. Well, thanks a lot, Nick, for joining. So we're obviously still enrolling into the study. So enrollment is ongoing and open for the study. We expect to be able to get to the initial assessment on the primary endpoint, which is the CR rate in the trial. And the CR rate is determined relatively early on as the life of patient [ expels ]. So we have 1 month after 1 month, the first measurement for the CR, for the tumor assessment and then 1 month later confirmation of that assessment, has basically confirmed CR rate, which is the primary endpoint, and that is happening very relatively close to the actual last patient dose. So that's going to be kind of the key focus of the first data that, I think, we can be -- we can talk about in the context of the trial. And then obviously, the second key part is, as you were pointing out is the observation over time, and we believe that, that's going to be the 6-month data point and we expect that data point to become available to the end of the year.

Great. Then going back to your 16 patients, how many of these patients required ICU admission within the first 28 days after obe-cel?

Edgar, do you want to take that?

There were only a few patients who really required an ICU administration. So it was lower than we have seen it with the ZUMA-3 study.

And Edgar, were those for CAR T-related events or disease-related?

Well, it was, to some extent, a mixture. Some of them were related to CAR T cell-specific toxicity and some was related to other events like, for example, infections and so on. What do you see normally in these kind of patient frequently.

Okay. And then just last one me. It looks like in the FELIX running, you had 3 patients with MRD positive disease. Obviously, it's too early to tell how those patients do. But in general, Christian, how is enrollment going in the MRD positive cohort? How excited are physicians to enroll patients in that cohort as opposed to the -- frank to these relapse cohort.

Right. So the way we're conducting the Phase II study is actually to focus, first, on the morphological cohort and then subsequently, we'll focus on MRD patients. And it's very interesting when you certainly talk to physicians, there's a high degree of interest to actually involve patients with low disease burden. But from a regulatory perspective for first approval, we need to get the morphological cohort down first. And so that's the focus for the current enrollment and subsequent, we'll be focusing on the MRD cohort broadly.

Your next question comes from the line of Mara Goldstein from Mizuho.

Just a question on FELIX and the Grade 3 ICANS event. Can you characterize that for us? And then in the NHL extension program, can you just talk about the use of pembrolizumab and as that relates to what you're seeing in terms of evolving standard of care for CAR T therapy?

All right. I'll start out with the question related to the Grade 3 ICANS. So the type of ICANS we've seen with obe-cel are consistent between ALLCAR and obe-cel study. And typically, what you do see is, I mean, it's a range, it can start it with tremors, the [indiscernible], confusion and it could go into -- if you go and wants to get to Grade 3s and Grade 4s, it can go into seizures. So that's the range, and that's sort of the evolution that you see or can see. What's important in both ALLCAR entry and FELIX is that patients responded very well to set with intervention and normalized very quickly, which is really, kind of, from a patient management perspective, if I think, the key element, which is a lot of confidence that it's a very -- very well controllable adverse event. You know what to look out for and you know how you intervene and you have a very effective way of controlling the adverse event. Second question was related to pembro and DLBCL. Obviously, we're giving, as Wolfram was pointing out, a single dose of pembro as part of the preconditioning regimen. Obviously -- and we had talked about in the context of AUTO3 belief that is a good support in that particular indication, whether that's something that we're going to see more broadly across other indications, I think it's too early to tell. Obviously, when we look at our own data in the follicular setting, certainly, business to -- given that we have everybody in metabolic CR, it doesn't seem to actually have a significant role play as far as we can tell at this point in follicular lymphoma. So that field needs to be watched going forward.

Okay. And if I could just ask a follow-up on the dual targeting program. I mean 2 cars are better than 1, and I get that. But maybe if you can just talk about what that clinical path forward is for this just in the context of what you see competitively out there right now?

Yes, I'm happy to do that. Maybe -- Edgar, maybe you want to outline what we're thinking about the pediatric development for AUTO1/22.

Yes. I think we'll be looking for -- I think if you -- as you all know, currently in pediatric ALL, [indiscernible] is standard of care, but you see that a significant number of patients are relapsing within the first year. And one of the major mechanism for relapse is the CD19 negative relapse. And so what we're basically looking for is, as Mike pointed out, we're currently doing a clinical study with our academic collaborator to use ALL. But what we're really looking for at this study is a long year as range. So -- and we were looking to [indiscernible], and we're also looking to how many patients have a CD19 negative relapse. And if we see a long effect on the event-free survival, for example, we see a low number of patients who have a CD -- not the CD19 negative relapse then we would move into a pivotal program for pediatric ALL with AUTO1.

Your next question comes from the line of Matt Phipps from William Blair.

First off, in the Phase Ib portion of FELIX, how many patients were treated or had frozen leukapheresis used in their manufacturing? And then I guess, will the Phase II portion all be fresh, for assistance?

Matt, thanks for joining. We have also 16 patients in total. And Wolfram, correct me if I'm wrong here, but I believe we had 6 patients that were manufactured from frozen lukes. With regards to the path forward, all of the lukes are going to be fresh in the Phase II portion of the study.

In the NHL cohorts, is that using kind of the original manufacturing process? Or are you kind of incorporating the industrialized process in that study as well?

This is -- the manufacturing process actually looks like the original manufacturing process on the prodigies for that we used in ALL. Remember, we have both -- we have also prodigies on the ALLCAR study but, obviously, with a slightly different process. The process we're using in the non-Hodgkin's patients is closer to the original manufacturing process that we used in the ALLCAR study. Obviously, you do not have the added challenge of high degrees of circulating tumor cells in non-Hodgkin's lymphoma. So the original process was well suited for these patients.

Okay. Got it. You mentioned the slide that you're continuing to enroll DLBCL and CLL patients, but do you plan on enrolling any more follicular or mantle cell?

We're currently looking into that. We're probably going to add additional patients on mantle cell and fill up quite likely follicular cohort as well. But -- so there's going to be a bit more in terms of data that we want to generate around those 2 cohorts as well.

Okay. For CLL, I mean there's, obviously, been some encouraging data with the BTK. Inhibitors are trying to increase the CR rate there. Is that something you'll consider?

I think for this part of the study, I think we want to understand the activity of the product on its own to get an understanding of what the profile is. As you point out, there are options going forward to consider actually adding BTK inhibitors as well. And certainly, in the case of Breyanzi, that seemed to actually increase the level of activity that was seen. But I think at this point, we want to understand the baseline activity of the product itself, and that's what we're still establishing.

Okay. And then lastly, with the first couple of CD19 CARs looking to move up to the second line DLBCL and just kind of the rest to move these forward. How do you think about competing in some of these non-option form of spaces?

Well, first of all, this is really -- I think the data was really great news overall for the field because it really showed that as you move up the line, the patients are less pretreated. And frankly, the quality of the T cells you're actually going to be isolating from their cells are substantially better. And as a consequence, your products tend to be more active. And of course, the disease is implied has progressed and therefore easier to catch up with. And I think to see the outcome against chemo plus stem cell transplant is remarkable. The clarity of the signals that we have seen at least in 2 of the studies. So that's really good news because it really tells us that there is something fundamental that we can do with this therapeutic modality across the non-Hodgkin's landscape. Now this is a pretty big space to actually be able to capture. So we think actually, there is a window of opportunity here that is actually going to extend, I think, for quite a bit of time. And we believe that products with the properties of obe-cel or there are some of also the new work that we're doing, I think we'll have an attractive opportunity to move forward. So that's -- I think that's sort of I think the way we think about it. But overall, I think, obviously, very good news for the field overall, and I think very good news for patients that there is a real alternative to the current stem cell transplant that may give you actually a much better outlook.

Your next question comes from the line of Kelly Shi from Jefferies.

This is Dave for Kelly Shi. I have a few questions. One is as AUTO1 moved to -- into follicular lymphoma, and you just mentioned other trials. In your opinion, what kind of improvement on both efficacy and safety would support a path forward in follicular lymphoma?

Dave, I think a really good question. I think what we're seeing, obviously, is that CAR Ts, in general, and follicular lymphoma tend to have a high degree of activity. Obviously, what we're seeing so far is exceptional with our product, combined with a good safety profile. And we believe in the context of, obviously, developing the product in ALL and building up the manufacturing base for the program, the commercial set up for the program. Obviously, there is considering a sort of a line extension into additional indications becomes attractive to think about. And we believe that the profile of the product could lend itself for that kind of an extension. So that's kind of the way we think about in the context of obe-cel. If you want to de novo -- go with the de novo program into the space, I think you have to aim for a level of activity that is -- certainly gets beyond what the current products can do in last line settings and typical third-line settings. And so to get beyond of what we currently see. And as you as an example, in DLBCL, we sort of see a ceiling almost at around 40% sustained CRs, irrespective of the product and, frankly, the modality. And I think if you want to go in with the de novo product, you probably would want to see an ability to sort of breakthrough that level of sustained CR rate to take a product forward if it's a de novo, completely new product.

Just one quick on ALLCAR19 versus FELIX. You just mentioned that a patient has a similar profile for both these programs. But could you characterize any noticeable difference in patient baseline that might have resulted in slightly lower rate of 75% and slightly lower T cell expansion? Or do you think it's just a small sample size?

I think it is, first and foremost, a small sample size question. As Edgar pointed out, there are some differences when you look at the patient composition that may point to somewhat more advanced patients and patients with higher tumor burden that we had in the FELIX 1b study. But frankly, given the patient numbers that we had in the study, I don't think you can actually -- you can actually see an actual difference between those 2. A swing of one patient basically moves to your percentage by at least 5%. So that tells you right there that one patient up or down basically gets you to the same place. And that, frankly, is arbitrary.

Your next question comes from the line of Eric Joseph from JPMorgan.

A few from us. Picking up on Edgar's comments about manufacturing and how you're able to make products from [indiscernible] material with a higher blast count compared to what you were able to do in the -- with the academic program. I'm curious to know how high of, I guess, patient's last count you can go to and build successfully make products and how that compares with Tecartus? Secondly, in the Felix Phase Ib data, can you just talk about how the composition of CR versus CRI compares with ALLCAR19? And is there a particular threshold of CR with complete count recovery that is important to achieve from a registration perspective?

Okay. I'll start out with -- and then we'll hand over to you, Edgar. So first off, on the manufacturing side, as I indicated before, we've been able to manufacture for all patients. And what we did see is that we did have patients who could be substantially above 90% of the cells in the leukapheresis Phase b and leukemic cells. So this can be enormously high if you have a very significant level of leukemics held at that it basically gets moved from the marrow line to the bloodstream. So it can be extraordinarily high. The process is designed to deal with that. Frankly, I cannot compare to Tecartus. I don't know whether that kind of data is actually available and has been discussed in the context of Tecartus. So I don't think we can make a commentary around that. CR/CRI split, obviously, we haven't shown for all color or for FELIX 1b study, but we expect to certainly show that for the FELIX study, and I don't know if, Edgar, whether you want to point out anything with regards to CR/CRI?

Well, I think we see a high degree of CR in our patient population, and -- which is very much in line what we have seen with the ALLCAR19 study. So I think we see a very high degree on CR rates.

Okay. And just going forward with the Phase Ib portion of FELIX, should we anticipate ongoing updates in the quarter '22 from that portion of the trial alongside the presentation of the Phase III portion?

Eric, I would expect that, obviously, the key focus on the presentations next year will be on the Phase II data, and also this is the primary focus of the updates. I'm sure in terms of total data around the -- across the entire study, obviously, we'll provide updates, for sure. But the primary focus in terms of data updates will be in the Phase II portion of the program as we go through the course of next year.

There are no further question at this time. You may continue.

All right. Well, thanks a lot for joining our call today. I know this is still a busy conference. We're in the middle of it. I wish you a successful conference and looking forward to connecting with you in person, hopefully, at the beginning of the year. All right. With that, we conclude our presentation, and thank you all for joining.

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