Hello, ladies and gentlemen. I am pleased to welcome you 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 of Autolus. Please go ahead.
Thank you. Good morning or good afternoon, everyone, and thank you for joining us in 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 Head of Clinical Development; Dr. Martin Pulé, our Chief Scientific Officer; and Andrew Oakley, our CFO.
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.
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. On slide three, 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.
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 was on obe-cel and the next-generation program called AUTO1/22. As you remember, obe-cel has a unique design and mechanism of action, and we believe actually has the potential to be a best-in-class CD19 CAR program.
The morphological event-free survival that we see with ALLCAR19 in these adult ALL patients is that we see the event-free survival stabilize at around 12 months. Actually as we get out to 24 months, now reaching 46% event-free survival at the two-year mark. We also provided an update on the initial portion of the FELIX study.
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. We also see a high level of clinical activity in both the trials.
In addition to focusing on our work that we're doing in ALL, and in particular in adult ALL, we also obviously are exploring the activity of the program in non-Hodgkin lymphoma patients, and we'll provide an update on that as well. I think key take-home messages are really that the program is very active in non-Hodgkin lymphoma.
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 by antigen loss of the CD19 target that we're using, predominantly with obe-cel or 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. We're now moving to slide number six.
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.
We also obviously had an opportunity to update you as we went through the course of this year also with peer-reviewed publications about the program as well. 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 towards that type of an approach in the U.S.
When we look overall in terms of the key outcomes and focus for 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 the 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.
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.
As I indicated, we expect to see data presented during the course of next year, updates from all of the trials—obviously the FELIX study, fundamental value step in terms of driving towards pivotal data in the adult ALL setting.
Thank you very much, Christian. Good morning and good afternoon to everyone. Julie, if you can move to slide number nine. 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.
To put it in other terms, the one-year overall survival rate is about 26%. Despite the fact that the potential only curative treatment which those patients have is transplantation, we have to be mindful that, number one, not every patient is eligible for transplantation, and transplantation is still associated with a significant mortality and morbidity.
There's inotuzumab, which is an antibody-drug conjugate against CD22, and recently the United States approved Tecartus based on the ZUMA-3 study. I will go very shortly to the data, which to some extent also confirms a high unmet medical need in this setting.
You see that the main toxicity associated, or one of the major toxicity, is in 14% hepatic veno-occlusive disease. Specifically because of the short duration of response, many patients are transferred to transplantation. You see that in both cases, in 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 relapse and refractory ALL. You see the response rate is 65%. The median duration of response is 13.6 months. You see there are some significant toxicity associated with that. Grade 3 CRS and higher, about 24%. Neurotoxicity Grade 3 and higher, about 35%.
What we know is that about 50% of all patients in the ZUMA-3 study was admitted to the ICU. 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 relapse and refractory adult ALL. The first study we conducted is the ALLCAR19 study. This was performed with our academic collaboration, the University College London. This was an academic study, and later, based on the very encouraging result we have seen, we started a company-sponsored program, which is this FELIX program. The FELIX study basically has two parts. One is a Phase Ib part, and then it has a Phase II part.
The data I will update you on today is basically on the FELIX Phase Ib part as for 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 draw your attention to one thing. We are using a split dose of obe-cel in both studies, and so depending on the disease burden we give different doses. You see at the blast count, if the disease burden is low, below 20% blast count at screening and day one, patient received 100 million, and then on day ten, 300 million cells, 310 million cells.
If we have a high disease burden on day one, the patient received 10 million cells and the second dose about 400 million cells. One additional difference between the ALLCAR19 study as well as the FELIX study is the initial manufacturing process we used for the ALLCAR19 data was an academic manufacturing process and we have now put it in-house and have industrialized the manufacturing process. Number one, to fulfill the regulatory requirement, but also to support the commercialization. One of the differences we have in this product is that we now are also in a better position to handle leukapheresis product with a higher leukemic blast count. If you move to the next slide, this is basically comparing the patient characteristics between the ALLCAR19 study as well as the FELIX Phase Ib study.
You see basically that both of the patient characteristics are quite matching. You see all of these patients are heavily pre-treated. You see the median prior lines of therapy is three. You see that many patients have been treated previously with blinatumomab, 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 blinatumomab previously. We also see that the patients which have been enrolled in the FELIX study, Phase Ib, had a higher disease burden. The median 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 number 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 in about 85%. In the FELIX study Phase Ib, it was about 75%. 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 study, obe-cel was very well tolerated and you see CRS any grade in the ALLCAR19 study, about 55%. In 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%. In the FELIX study Phase Ib, 13%. If you look to Grade 3 ICANS, there were about 15% in the ALLCAR19 study and in the 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 the 35%. Now, on the right part of the slide, you see the CAR T-cell persistence, and you compare—we're comparing again to ALLCAR19 study. As a measure for the comparability, we're using Cmax here.
You see that in both studies, the Cmax data are quite comparable. The same is true for the AUC data. If you go to slide number 14, this basically gives you an update about the durability of response we have seen in the ALLCAR19 study. On the left side of the slide, you see the persistence of the CAR T cells. You see, as it has been shown in the publication in JCO in August of this year, basically a long persistence of the CAR T cells. It's been going up to 24 months in this publication. This long durability of persistence of the CAR T cells translates into the long durability of response.
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 drop stabilize at 12 months, and then it's stable up to 13 months. It's a very long durability of response. If you move to the next slide, which is slide number 15, I think what we have seen here is a very consistent results between the ALLCAR19 study as well as the FELIX study Phase Ib, the Phase Ib part of the study, in both safety as well in efficacy. 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. We see an excellent safety profile with no Grade 3 CRS and with a very low number of Grade 3 ICANS. We also see in the ALLCAR19 a long persistence which is driving the long durability of response. We, as Christian already pointed out, are now in the Phase II part of the FELIX study, which is our pivotal program, and the study is currently actively enrolling patients. We will report about the data of the FELIX study, the Phase II part by mid-2022. As Christian also pointed out, we have engaged in regulatory interaction. We received the ILAP designation in the U.K. from MHRA, as well as PRIME designation in the EU.
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. In the lymphoma program, this is part of the ALLCAR19 study. These are extension studies. In contrast to the adult 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 one single dose of pembrolizumab in order to deepen the persistence and the engraftment of the CAR T cells. In the B-cell 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 on day 9 to mitigate the risk for severe CRS or ICANS.
If we go to the next slide, please, slide number 18. This shows the B-NHL and the CLL cohort, 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, and you can see on the right-hand side, the median age is roughly 60 years. It's more or less consistent with what is the standard population in this relapsed refractory setting. We have treated seven patients with follicular lymphomas, four patients with diffuse large B-cell lymphomas, including a couple of patients with transformed follicular lymphoma, and three patients had mantle cell lymphomas. Currently, two patients with CLL, with relapsed refractory CLL, were dosed with AUTO1.
The median number of prior lines of treatment was 3, with a range of 2-5, and almost all patients received a bridging therapy. The lymphoma patients mostly a chemo-immunotherapy regimen, and one patient only received rituximab, which is an immunotherapy only. If we go to the next slide, please. Slide number 19. You can see the favorable tolerability profile of obe-cel in the lymphoma patient, which is consistent with what we have seen also in the ALL cohort. There were no ICANS and no severe CRS syndrome in any of these patients. Really consistent with what we have seen before, and, importantly, no new safety signals were observed. If we go to the next slide, number 20, this shows the excellent T-cell expansion and engraftment in these lymphoma patients, in the B-NHL patients, up to nine months.
The Cmax is pretty high, as you can see on the right-hand side of the table. If we go to slide number 21, this shows the encouraging efficacy and the duration of response in these non-Hodgkin lymphoma patients and the two patients with CLL. On the left-hand side, you can see in the swim plot the seven patients with follicular lymphoma. All of them achieved a complete response, complete metabolic response. You see the three 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. Again, as the best response, all of the three patients had a complete metabolic response. Likewise, the patients with diffuse large B-cell lymphoma or transformed follicular lymphomas, they also had a complete metabolic response.
One patient is still pending. This is indicated with a gray bar, as you can see on the slide. Also, there was one patient where the disease assessment is not reached because it's simply too early. The other patient with CLL in the blue bar has achieved a partial response with the 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 and the DLBCL patients. It's roughly 12 months with a broad range from 2-14 months. For the MCL cohort, it's about 7 months with a range of 1-15 months. If we go to the next slide, please, number 22.
In summary, obe-cel 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 who are available for efficacy, the response rate is 100%, and the overall metabolic complete response rate is 93%, 13 of the available 14 patients. We have seen long-term persistence of obe-cel demonstrated by qPCR, and 15 of 16 patients are ongoing without disease progression. Six of the seven patients in CR have a duration for more than 10 months, and one 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 Pooley.
Thank you, Wolfram, and hello, everybody. If we can move to slide 24, please. Many of you will know that we tested obe-cel previously in children with relapsed refractory B-ALL. We published this data in Ghorashian et al. Nature Medicine in 2019. What we found in this study is that obe-cel in this setting had the same nice properties of low toxicity and excellent engraftment. However, children tolerate immunotoxicity much better than adults. 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 two antigens simultaneously. The second antigen that is most logical to target is another B lineage antigen, which is CD22.
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 synapse difficult. Secondly, it's normally expressed at about a log lower than CD19, and furthermore, after challenge with CD22, it down-regulates even further to less than 1,000 copies per cell. We go to the next slide 25. We invested quite a bit of time developing a CD22 CAR that was sensitive to very low density CD22.
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 that 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 and T-cell proliferation in response, again, to low density CD22 targets. 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 transduction.
What this simply means is during the manufacturing process, rather than just adding one vector which encodes for the CD19 CAR for obe-cel, we add two vectors. One which encodes obe-cel, and one which encodes a 9A8, a 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 it 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 four populations. Non-transduced cells, double transduced, and single transduced. This is actually quite nice in a way because we can study the relative engraftment of the different cell populations of CAR T cells in patients.
If any of you have seen our poster, you'll have seen 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 the ALL using NALM-6 cells, and you can see that AUTO1/22, the co-transduced product, performs well in this setting, perhaps even better than obe-cel alone. Below we're showing a model of CD19-negative escape where CD19 is knocked out from the NALM-6 cells. There you can see as expected, obe-cel doesn't work at all, because there's no CD19, but AUTO1/22 clears the tumor very nicely. We started testing this in patients.
What I'm showing here is 6 FACS plots at day 28 from the 6 patients that we've treated so far with this product. This FACS 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. Here you can see very nice engraftment of all the different subpopulations of CAR T cells in all of these patients at day 28. 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 escapes. The six patients we've treated. We've dosed six patients so far and all show engraftment of both single and double CAR T-cell population by flow cytometry. With that brief summary, I'll hand back to Christian. Thank you very much.
Moving to slide 31. We have a very consistent picture regarding the properties of obe-cel, which builds on a unique mechanism of action: a "fast off" kinetic from the CD19 target. This gives us a high level of activity without over-activating the CAR T-cell, resulting in a much better safety profile and allowing the product to expand more. In the ALLCAR study, we saw that at the peak, we have about 10 times the number of CAR T-cells compared with competitive products, allowing for better persistence and avoiding cell exhaustion.
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 10 times the number of CAR T-cells that we actually see in our patients compared with any other competitive products in this space. It also actually allows us a much better persistence over time. Obviously finally also by avoiding this high degree of over-activation, we also avoid exhaustion of the CAR T-cells and overall have a much healthier product. Now that translates obviously in an interesting set of activities.
The updated event-free survival (EFS) data shows stabilization at 12 months, and at 24 and 30 months, we remain at 46% EFS. No other therapy has demonstrated this stabilization in adult patients with ALL. Regarding our pivotal FELIX study, the phase Ib portion demonstrated that industrializing the process in a multicenter environment maintains the same level of activity and safety. In the NHL expansion, we are seeing 100% metabolic complete remissions. In follicular lymphoma, at around 10 months of observation, all patients remain in continued remission.
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 the same level of activity and, safety profile as we've seen in the old CAR study. We're building obviously on that as we're now, 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 activity in CLL, obviously more data to be generated in those indications. 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 would point to kind of an attractive opportunity downstream, the ALL activities that we currently have ongoing.
We are also building on the lifecycle management of AUTO1/22, which adds a highly potent CD22 CAR to the obe-cel backbone to counteract relapses due to antigen loss. We expect data updates from all studies throughout next year, with the primary focus on the pivotal data from the FELIX study. I will now ask the operator to initiate the Q&A.
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. With that, I think we're at the end of our presentation today. What we'd like to do is actually open up for question and answers. I'd like to ask the operator to initiate the Q&A. Thank you.
At this time, if you would like to ask a question, press star, then the number one on your telephone keypad. Again, it's star one on your telephone keypad. We'll pause for just a moment to compile the Q&A roster. Your first question comes from the line oGil Blum [Senior Biotech Analyst]
Good morning. Was the lead-in portion in FELIX requested by a regulatory agency, or was it always the plan to show comparability before moving to phase II? Also, can you confirm there were no production failures?
The phase Ib was planned from the start. We transferred the manufacturing process to handle leukapheresis from patients with high circulating leukemic cells and switched to a commercial vector. This required a run-in to demonstrate comparability before transitioning to phase II. And yes, that is correct: we have had no production failures and were able to manufacture for all patients.
There's significant changes that we made to the overall manufacturing process in terms of the specifics of the process. That also obviously required us to do a run-in 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. 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.
Regarding indolent lymphomas, do you think the safety profile will be differentiating, given other cellular therapeutics in the space? And a question for Martin: any thoughts on the higher pre-clinical activity seen with AUTO1/22 versus AUTO1?
A good safety profile is a prerequisite for indolent lymphoma because many other treatments are given in an outpatient setting. CAR T offers a one-time intervention that can induce true long-term remission, which is very different from the weekly therapy typical for follicular lymphoma. Regarding AUTO1/22, the edge comes from the high potency of the CD22 CAR. Having two CARs provides an advantage given the varying expression levels of CD19 and CD22 in vivo.
Remember, this is a one-time intervention that so far we're collecting 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 till relapse with the current regimens. We believe this is going to become an attractive space, contrary to what probably a lot of people believed for a while back. With the ongoing persistence and the ongoing clinical responses, we believe there is a very interesting opportunity slowly opening up here for CAR T therapies in that space.
Great. Maybe one last one for Martin, just something I saw at the poster. Any thoughts as to the higher activity that you're seeing pre-clinically with the AUTO1/22 versus AUTO1?
Maybe two CARs are better than one.
Maybe. All right. I think that's it.
Okay. You know, Gil, what it speaks to is the very high potency of the CD22 CAR. That clearly seems to have a beneficial effect here. 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. To Martin's point, having two CARs in that situation actually gives you an advantage. That's probably from a, let's just think about it from a theoretical perspective, certainly where you would think the edge would come from.
I'll stick with two is better than one. All right, guys. Thanks for taking my questions.
All right, Gil. Thanks a lot.
Your next question comes from the line of Nick Abbott from Wells Fargo Securities . Your line is open. Please ask your question.
Good morning. Christian, with the FELIX data in mid-2022, can you update us on enrollment for that pivotal cohort and the expected follow-up? Also, how many of the 16 patients required ICU admission within the first 28 days?
Enrollment is ongoing. We expect to reach the primary endpoint—the confirmed CR rate—relatively close to the last patient dose. The second key part is the observation over time, and we believe that six-month data point will be available by the end of the year. Edgar, do you want to take the ICU question?
That's gonna be kind of the key focus of this, the first data that I think we can talk about in the context of the trial. Then obviously the second key part, as you were pointing out, is the observation over time, and we believe that that's gonna be the six-month data point. We expect that data point to become available to the end of the year.
Great. Thank you for the clarification. Going back to your 16 patients, you know, 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 required an ICU admission; it was lower than what we have seen with the ZUMA-3 study. It was a mixture of CAR T-cell specific toxicity and other events like infections.
Edgar, were those all 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 you see normally in these kind of patient frequently.
How is enrollment going in the MRD-positive cohort? How excited are physicians to enroll those patients as opposed to the frank disease relapse cohort?
The phase II study focuses first on the morphological cohort for regulatory reasons, and subsequently we will focus on MRD patients. There is a high degree of interest from physicians to enroll patients with low disease burden.
Great. Thank you very much.
All right. Thanks, Nick.
Your next question comes from Mara Goldstein from Mizuho Securities.
Can you characterize the grade 3 ICANS event in FELIX? Also, can you talk about the use of pembrolizumab in the NHL extension and the clinical path forward for the dual targeting program?
The types of ICANS seen are consistent with the ALLCAR study, ranging from tremors and confusion to seizures in grade 3 or 4. Crucially, patients responded very well to steroid intervention and normalized quickly. Regarding pembrolizumab, we are giving a single dose as part of preconditioning. In the follicular setting, everyone reached metabolic CR, so it does not seem to play a significant role there yet. Edgar, do you want to outline the pediatric developments for AUTO1/22?
Okay.
In this study. Typically, what you do see is, I mean, it's a range, you know, can start with tremors, aphasia, confusion, and it can go into. Once you 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 and FELIX is that patients responded very well to steroid intervention. It normalized very quickly, which is really kind of from a patient management perspective, I think the key element, which give you a lot of confidence that, you know, it's a 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 FIM or the obe-cel. Obviously, we're giving, as Wolfram was pointing out, single dose of pembro as part of the preconditioning regimen. Obviously, we had talked about in the context of AUTO3 we believe that is a good support in that particular indication. Whether that's something that we're gonna see more broadly across other indications, I think is too early to tell.
Obviously, when we look at our own data in the follicular setting, certainly it doesn't seem to, you know, 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.
Mm-hmm.
That field needs to be watched going forward.
Okay. If I could just ask a follow-up on the dual targeting program. I mean, two CARs are better than one, and I get that, but maybe you can just talk about you know what that clinical path forward is for this, just in the context of what you see competitively out there right now.
Yeah, I'm happy to do that. Maybe, Edgar, maybe you wanna outline how we're thinking about the pediatric developments for AUTO1/22.
In pediatric ALL, Kymriah is the standard of care, but many patients relapse within the first year due to CD19 negative escape. We are conducting a study at UCL looking for a long EFS range and a low number of CD19 negative relapses. If successful, we would move into a pivotal program.
If we see a long effect on the event-free survival, for example, and we see a low number of patients who have a CD19-negative relapse, then we would move into a pivotal program for pediatric ALL with AUTO1/22.
Okay. Thank you.
Thanks, Sarah.
Your next question comes from Matt Phipps from William Blair.
In the phase Ib portion of FELIX, how many patients used frozen leukapheresis? Also, in the NHL cohorts, are you using the original manufacturing process or the industrialized one?
We had 16 patients total, and six patients were manufactured from frozen leuks. All leuks will be fresh in the phase II portion. In the non-Hodgkin patients, the process is closer to the original Prodigy process used in ALLCAR. We do not have the challenge of high circulating tumor cells in NHL, so the original process was well suited.
Yeah.
-manufactured from frozen leuks. With regards to the path forward, all of the leuks are gonna be fresh in the phase II portion of the study.
Thanks, Kirsten. 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?
The manufacturing process actually looks like the original manufacturing process on the Prodigy that we used in ALL. Remember, we have also Prodigy involved on the ALLCAR study, but obviously with a slightly different process. The process we're using in the non-Hodgkin 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 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 gonna add additional patients on mantle cell and fill up quite likely follicular cohort as well. There's gonna be a bit more in terms of data that we want to generate around those two cohorts as well.
Okay. Well, for CLL, I mean, there's obviously been some encouraging data with the BTK inhibitors to try to increase the CR right there. Is that something you'll consider?
I think for this part of the study, I think we wanna 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. Certainly in the case of TRANSCEND, that seemed to actually increase the level of activity that was seen. I think at this point we want to understand the baseline activity of the product itself, and that's what we're still establishing.
Lastly, with the first couple CD19 CARs moving to second-line DLBCL, how do you think about competing in the NHL space?
The data is great news for the field because it shows that as you move up the line, the T cells are better quality and more active. To see the outcome against chemo plus a stem cell transplant is remarkable. We believe there is a window of opportunity that will extend for quite some time, and products like obe-cel will have an attractive opportunity to move forward.
That's really good news because it really tells us that there is something, you know, fundamental that we can do with this therapeutic modality across the non-Hodgkin landscape. Now, this is a pretty big space to actually be able to capture. We think actually there is a window of opportunity here that is actually gonna extend, I think, for quite a bit of time. And we believe that, you know, products with the properties of obe-cel or some of the, also the new work that we're doing, I think will have an attractive opportunity to move forward. That's, I think that's sort of, I think the way we think about it.
Overall, I think, obviously, very good news for the field overall, and I think very good news for patients that, you know, 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 Kalisi from Jefferies. Your line is open. Please ask your question.
Hi. Thanks for taking the question. This is Dave for Kelly. I have a few questions. One is, as AUTO1 moved 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?
Hi, Dave. I think a really good question. I think what we're seeing obviously is that CAR Ts in general in 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. We believe in the context of obviously developing the product in ALL and building up, you know, the manufacturing base for the program, the commercial setup for the program. Obviously there is—considering a sort of a line extension into additional indications becomes attractive to think about. We believe that the profile of the product could lend itself for that kind of an extension.
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 of what the current products can do in last-line settings and, you know, typical third-line settings. To get beyond of what we currently see, and as an example in DLBCL, we sort of see a ceiling almost around 40% sustained CRs, irrespective of the product and frankly, the modality.
I think if you want to go in with a de novo product, you probably would want to see an ability to sort of break through that level of sustained CR rate to take a product forward if it's a de novo completely new product.
Thanks for the answer. Just one quick on ALLCAR19 versus FELIX. You just mentioned that patient has similar profile for both these program, 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's some differences when you look at the patient composition that, you know, may point to somewhat more advanced patients and patients with higher tumor burden that we had in the FELIX Ib study. But frankly, given the patient numbers that we had in the study, I don't think you can actually see an actual difference between those two. You know, a swing of one patient basically moves your percentage by at least 5%. So that tells you right there that, you know, 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. Your line is open. Please ask your question.
Hi. Good morning. Thanks for taking the questions. A few from us. Picking up on Edgar's comment about manufacturing and how you're able to make products from leukapheresis material with a higher blast count compared to what you were able to do in the academic program. I'm curious to know how high of a patient's blast count you can go to and still successfully make product and how that compares with Tecartus. Secondly, in the FELIX Phase I, 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?
I'll start out with you know and then we'll hand over to you, Edgar Braendle. First off, on the manufacturing side, you know, as I indicated before, we've been able to manufacture for all patients. What we did see is that we did have patients who could be substantially above 90% of the cells in the leukapheresis being leukemic cells. This can be enormously high if you have a very significant level of leukemic cell that basically get moved from the marrow into the bloodstream. It can be extraordinarily high, and the process is designed to deal with that. Frankly, I cannot compare to Tecartus.
I don't know whether there's 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 obe-cel or for the FELIX Ib study. But we expect to certainly show that for the FELIX study and I don't know if Edgar whether you wanna 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 with what we have seen with the ALLCAR19 study. I think we see a very high degree of CR rates.
Okay. Just going forward with the Phase Ib portion of FELIX, should we anticipate ongoing updates into the course of 2022 from that portion of the trial, alongside presentations of the Phase II portion? Thanks.
Eric, I would expect that obviously the key focus on the presentations next year will be on the Phase II data. Also will be the primary focus of the updates. I'm sure in terms of, you know, total data around, across the entire study obviously we'll provide updates for sure. 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.
Okay, got it. Thanks.
Okay. Thank you.
There are no further questions 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 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.
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