Autolus Therapeutics plc (AUTL) Earnings Call Transcript & Summary

Hello, ladies and gentlemen, and welcome to the Autolus Therapeutics ASCO Analyst Conference Call. As a reminder, this conference call is being recorded. [Operator Instructions] I would now like to turn the conference over to your host, Olivia Manser. Please go ahead.

Thanks, Andrew. Good morning or good afternoon, everyone. Thanks for joining us on a Saturday to discuss our data from the pivotal FELIX study of obe-cel, which was presented yesterday at the ASCO Conference. With me today are Dr. Christian Itin, our Chief Executive Officer, and we're really grateful to have Professor Claire Roddie, Associate Professor of Hematology and Honorary Consultant Hematologist, Cancer Institute UCL, University College London, on the call today to walk through the data that we presented yesterday. So on Slide 2. Before we begin, as usual I just want to remind you that during today's call, we will make statements related to our business that are forward-looking under federal securities laws and the safe harbor provision of the Private Securities Litigation Reform Act of 1995. These may include, but are not limited to, statements regarding the status of clinical trials and development and/or regulatory timelines for our product candidates. These statements are subject to a variety of risks and uncertainties that could cause actual results to differ materially from expectations and reflect our views only as of today. We assume no obligation to update any such forward-looking statements. And for a discussion of the material risks and uncertainties that could affect our actual results, please refer to the risks identified in today's or yesterday's press release and our SEC filings, both available on the Investors section of our website. So on Slide 3, you'll see the agenda for today's call. Christian is going to set the field on obe-cel and the FELIX study results to date and Dr. Roddie will then run through the slides that were presented yesterday in an oral presentation at ASCO and Christian will then close the call before we take Q&A. So over to you, Christian.

Thank you very much, Olivia, and welcome, everybody, to our call this morning from ASCO. It's a pleasure to have you all on and also a pleasure to have Claire actually walk us through the data presented yesterday. On Slide 4, just a quick overview where we are with the company and where we stand with the program overall. As you remember, we did our first presentation of the FELIX data, the first data cut that we had of the full study a year ago at ASCO here in Chicago as well and we're now obviously at a point where we have substantially more follow-up data and that's going to be really the key part of the topic for today. And also start to develop a very good understanding of some [indiscernible] and some of those aspects will be highlighted today in Claire's talk. Just as a background. You may remember that we had filed for an approval in the U.S. as well as in Europe. The PDUFA target date in the U.S. is November 16 of this year and that's obviously ongoing process and review process that we're in the midst of and just a bit over half time in that review process. We're pushing obviously the program further into additional indications so there's going to be more updates towards the end of the year in that regard. We also have announced obviously that we have received a license from the U.K. agency, the MHRA, for the production of obe-cel at our new manufacturing facility, The Nucleus in Stevenage in the U.K and are obviously now in the process of preparing for launch and make sure we're ready by the time we get through that approval. Finally, obviously we have also announced earlier this year a set of transactions. Obviously an important transaction for us with BioNTech as well as a capital markets transaction, which puts the company [indiscernible] and gives us a strong foundation to be in a position to launch the product once we achieve and receive the approval. So what I'd like to do going on to Slide #5 is just briefly look at a few aspects of the data that we have presented at the end of last year and these are areas that I would say are key aspects of properties of the product that we're not going to be actually repeating on in today's presentation, but obviously are important to sort of keep in mind. Going on to Slide #6. Just to kind of remind ourselves actually when this study was actually conducted, when the patients were involved and were being treated. And in fact as you remember, we did actually start enrolling into the Phase I portion as of June 2020 and then actually finished the Phase II portion involvement at the end of November 2022. So we're kind of in the height and through the height of the pandemic and you could see on this chart in the blue charted area, we see the various peaks that we had seen on infections that we all have a collective memory on how that was. But also what I think is important, it gives us a sense of how massive the impact actually was on a lot of aspects. In this case, one of the parameters is obviously international flights from the U.S. As you can see in the green line that there was huge fluctuations in availability of flights between the U.S. and obviously in this case our manufacturing site in the U.K. from which we supply. Now despite all these fluctuations, all these challenges in logistics, et cetera; we're able to actually have very steady supply of the product with very consistent length of delivery times throughout the entirety of the trial. We see this little fever chart in the middle. There you see literally every individual product plotted over time and the actual length of delivery time that the product actually had over that period. So we were able, despite all of this very volatile background, to actually deliver very steady, very consistent product throughout the entirety of the study. And that's obviously an important aspect as we prepare for commercialization is that a lot of the systems that we build, the product delivery capabilities, the logistics, et cetera, have been pressured tested to an enormous extent during the [indiscernible] therapy. The other aspect I think I just want to highlight here is obviously one of the things that we were certainly very mindful about as we were conducting this study during this period was that we had to actually be aware that there was a lot of things that could happen during that period. We had many of the hospitals shut down at one point or another, were not able to recruit patients, were overwhelmed with too many infections, their ICUs were overwhelmed, et cetera. So there's a lot of variability in there. And as a consequence, we also made sure that as we were setting up this study that the physicians would have an ability to actually manage the patients in the best way possible and with as much flexibility as possible. And this is also why we didn't put in any constraints with regards to their ability to bridge patients and also included very active agents like inotuzumab and allowed those for the bridging therapy. This is important because obviously it creates a backdrop within the study, which is a very real world type of backdrop and I think is also what resonates very well as we're sort of presenting the data now in various venues. So I'd just like to highlight 3 items or 3 features of the program and then we're going into the update that Claire will present. Going on to Slide #7. One of the hallmarks that we started to build and we started to actually see develop over time is that it looked like we're starting to see a stabilization of event-free survival in the patients that were treated on the FELIX study, which would be indicative that indeed there is a proportion of patients that have a chance for long-term outcome. This is a curve that's reminiscent and in fact was superimposable to the curve that we had seen in the ALLCAR19 study, the Phase I experience that we have that led into this pivotal program. Now obviously as we were at ASH end of last year, there's still a limited number of patients who are in the outer part of the curve and also getting more follow-up will give us much more confidence around the ability to really predict longer-term outcome in the study. Now when we look more closely on the next slide and we're asking the question, what is the impact of tumor burden and lymphodepletion on the outcome? What you can see is that patients have in the blue curve tumor burden below 5%, that those patients had a remarkable chance for long-term outcome and you see that EFS stabilizes at around 70%. Patients that were sort of the intermediate range between 5% and 75% of tumor burden and lymphodepletion are the green curve and you can see they're still hovering around 50%, maybe slightly above it. It's only the patients that have very extreme levels of tumor burden of 75% after bridging therapy and are basically refractory to bridging therapy. What you can see with those patients is that they still have an overall remarkably positive outcome when you look at event-free survival, but clearly running below the patients that have lower levels of tumor burden. So give us a good indication of the impact of tumor burden and lymphodepletion on ultimate outcome with these patients. The other aspect, which is clearly a hallmark on Slide 9 of FELIX of obe-cel and what we were observing both in the ALLCAR study, but also in the FELIX study now is that the product has a remarkable safety profile. Here we're looking at hematological toxicities and we look at cytokine release syndrome and neurological toxicities reported as ICANs. And what you can see is that overall the high grade levels, which are the dark colors on the left hand side, are very low. We had 2% of patients experience high grade CRS, we had 7% experience high grade ICANs. This is actually a level of immunological toxicity that is numerically below of what was reported for Blincyto. So this is quite remarkable. Now when we then look at how these events actually were distributed across the level of tumor burden and lymphodepletion, what you can see is that with increasing levels of tumor burden, you see also an increased level of immunological adverse events, but overall it is still low. So even patients that have more than 75% tumor burden had in the range of 3% to 4% high grade cytokine release syndrome. So still very limited and very different from the experience that the field had with other CAR T programs. When we look at ICANS, again very limited levels and in fact when you look overall at the numbers for above 75%, those actually are still very much in line with not the high dose and not the high tumor burden experience, but the overall experience that physicians have with Blincyto. So it is a remarkable profile. It also indicates that patients that have very low tumor burden below 5% have a remarkable safety profile and combine that obviously with a remarkable event-free survival that we have seen on the slide before. So these are some of the hallmarks that we have seen. Those are part of the analysis that we have shared at the end of last year. So the focus of this presentation is somewhat different. It looks more into the longer-term outcome, but it also starts to look at the impact that we would see with additional therapies that the patients may experience. So with that, I'd like to actually hand over to Claire and move to Slide #10.

Thanks, Christian. So thanks very much for inviting me to share the data. So it's great to see it mature the way it has been. If we move on to Slide 11, that's our title slide for the presentation delivered yesterday. So essentially what we're talking about in this presentation is it's the obe-cel in the context of adults with relapsed and refractory B-cell Acute Lymphoblastic Leukemia, which obviously we've spoken about in previous occasions and here we're looking at the persistency and really the impact of consolidated stem cell transplantation in the context of our FELIX study. So if we can move on to Slide 12, please, and essentially this is a really helpful slide because it's just giving you sort of like a perceive of what we really feel are the main takeaway messages here. And I suppose the first most important thing to say is that after obe-cel infusion and this is at a median follow-up of 21.5 months now that 40% of responders were in ongoing remission and that's without subsequent allogeneic transplant or other therapies. It's important to note that both the event-free survival and the overall survival outcomes to the potential for a long-term plateau, which is of course something that was very exciting about the ELIANA study in pediatrics and so we are really sort of heartened to see this sort of a similar plateau emerging in the adult ALL setting. And today really the focus is on presenting data showing that constant consolidation for patients in remission following obe-cel doesn't seem to confer better survival outcomes, but we'll go into that in subsequent slides. Additionally, a really important take-home message here is that ongoing CAR T cell persistence was associated with improved event-free survival in this analysis. And so if we move over on to Slide 13 now and a lot of the callers will be familiar with this background. But essentially obe-cel, as we know, is a unique CD19 targeting autologous CAR T therapy and with this path of CD19 binding, it was really sort of designed to improve CAR T persistence and reduce the immune-mediated toxicity Christian was mentioning before. It's under investigations. We know when adults with relapsed and refractory Acute Lymphoblastic Leukemia in the context of this FELIX study and the FELIX study's been an open-label multicenter single-arm Phase Ib/II study. Now the safety profile of obe-cel also evaluated in FELIX has previously been presented in detail and it won't particularly be discussed during this presentation. Instead today, I'll really be focusing on event-free survival, overall survival and really the impact of CAR T persistence on stem cell transplant in these patients treated with obe-cel. And so if we move on to Slide 14. This is really our study design slide and it's showing us the sort of tumor burden-guided split dosing that we previously discussed. The split dosing as we know is based on the prelymphodepletion tumor burden such that on day 1 patients with 20% or less bone marrow blasts and i.e. low tumor burden and were able to receive a higher initial dose of CAR T cells at 100 million cells while those with over 20% blast or high tumor burden received a lower initial dose of 10 million CAR T cells. But on day 10 if the CRS was grade 1 or lower and ICANs were completely resolved, the second dose i.e. dose 2 of obe-cel could be administered in that setting. And then in the low tumor burden category, those patients would receive 310 million CAR T cells while those in the high tumor burden category received 400 million CAR T cells to a total of 410 million CAR T. And if we move on to Slide 15 now. So this slide is really just summarizing the patient eligibility and endpoints. And across the Phase Ib and II of the FELIX study, obe-cel was administered to a total of 127 adult patients and the patients were enrolled into 3 main cohorts and that depended on their disease characteristics and screening. So Cohort A comprised patients who had at least 5% bone marrow blast or morphologic disease and Cohort B comprised patients who were MRD positive and that they had greater than 10 to the minus 3 leukemic cells by NGS testing, but fewer than 5% bone marrow blasts by morphology or flu. And Cohort C comprised patients with isolated extramedullary disease. The primary endpoint was the rate of CR and CRi and that was conducted by independent review and secondary end points included duration of remission EFS, overall survival and MRD negativity rate defined as less than 10 to the minus 4 leukemic cells. And of course we were also focused in secondary endpoints in safety, CRT persistence and manufacturing feasibility. If we move on to Slide 16, here we're actually looking at the patient baseline characteristics and I think we can all agree looking at this slide that this is a heavily pretreated patient data set. And so these are all the infused patients included in Cohort IIA, that's those patients with more than 5% bone marrow blast. And this is really used for the primary efficacy analysis of FELIX and all the 127 infused patients included across the Phase Ib and II. Now the median age was 47 years for all of the infused patients. And as you can see here, the median number of prior lines of therapy was 2 and that varied from 1 up to as many as 6 lines of prior treatment. 42% of these patients had previously received blinatumomab, 31% had received inotuzumab and 17% have received both. 44% of these patients have had a prior stem cell transplant and that screening the median bone marrow blast percentage was 40% whilst extramedullary disease was reported in 23% of our patients here. Now if we move on to Slide 17. Here what we're looking at is really the response rates observed across the study. So of the 127 patients who received the obe-cel infusion, that's 99 patients or 78% achieved either a complete response or a CRi and that was determined by independent review by the data cut of February 7 of this year and that was with a median follow-up after obe-cel infusion of 21.5 months. Now at the current follow-up, the majority of responders are showing durable response. Amongst the 99 responders, 40% were in ongoing remission and that's without consolidated ALLO transplant or other therapies and only 18% actually went on to have a consolidative transplant whilst in remission. If we move on to the next slide, that's Slide 18. Here we're looking at event-free survival and actually for the main analysis, the median EFS and this is with sensoring post-transplant was 11.9 months with an estimated 12-month EFS rate of 49.5%. Now if you press next, you should be able to see the second curve emerge that's in green and when you look at this, it's the EFS without censoring for subsequent transplant and it looks from the position of this green line on the curve here that the consolidative transplant did not seem to improve EFS in patients post obe-cel. Now the median time to transplant was 101 days and this is after obe-cel infusion and all 18 patients who went on to have a consolidative transplant whilst in remission were MRD negative prior to the ALLO graft and of whom 80% relapsed or died post ALLO ASCT. Now of note there was no difference in patient characteristics between those who have not received a subsequent stem cell transplant. Now the last point I make about this slide is that 56% of the 18 patients have ongoing CAR T persistence prior to the transplant and 80% of the patients who had the ASCT relapsed or died after the transplant. And it is important I think for everyone to be aware of the fact that the transplant conditioning therapy tends to eliminate CAR T cell persistence and that's clearly an issue in terms of the ongoing immunosurveillance. And so if we move on to Slide 19 now. So here we're looking at overall survival and again it's really showing us that nice potential here for a long-term plateau. Now when you look at the OS, the median survival here without sensoring for subsequent ALLO transplant is 15.6 months with an estimated 12-month OS rate of 61%. And if we hit next slide, we should be able to see the green curve emerging and what this is showing us is the EFS where there's very little difference when we're looking at an overall survival with sensoring or without sensoring. So implying the consolidative transplant for patients post obe-cel does not actually improve the overall survival. The potential of long-term plateau is seen for both overall survival and EFS and that's similar to the trends that we've observed already in the Phase I ALLCAR19 study, which also investigated obe-cel in adults with relapsed and refractory Acute Lymphoblastic Leukemia. Now if we move on to Slide 20. Here we're looking at CAR T cell persistence and predicted relapse. Now in order to understand the impact of loss of CAR T cell persistency on EFS, we performed COX regressions and that was using loss of CAR T cell persistence by digital droplet PCR as a time-dependent covariant. Now a similar analysis was also conducted for B-cell recovery and what we found here was that ongoing CAR T persistence and B-cell aplasia were both associated with improved event-free survival. And as indicated by this hazard ratio shown on the left panel, the risk of relapse or death would be 2.7x as high upon loss of CAR T persistence compared with patients with ongoing CAR T persistence and its impact was superior to B-cell aplasia. And similarly, as indicated by the hazard ratio shown on the right panel, the risk of relapse or death would be 1.7x as high once patients have B-cell recovery. Now of note, the 95% confidence interval did not exclude 1 and it is a numerically smaller effect compared with loss of CAR T persistence. Now if we move on to Slide 21. We're looking here at the landmark analysis amongst patients in ongoing remission at 6 months and this is without transplant or new therapies. And really what comes out of this slide and what's most notable is that patients with ongoing CAR T cell persistence are associated with improved EFS compared with patients who lost CAR T persistence. And in fact the median EFS for patients with loss of CAR T persistence was 15.1 months while the median was not yet reached for those with ongoing CAR T persistence. So clearly emphasizing how important the persistence is to the ongoing event-free survival in this group. Now next slide is Slide 22 and here we're really concluding. So it's really to summarize what we've just looked at. So with the current median follow-up of 21.5 months, 40% of responders were in ongoing remission without subsequent stem cell transplant or other therapies. The primary analysis, 12-month EFS and overall survival rates were 49.5% and 61.1%, respectively. Now these survival outcomes also show the potential for the long-term plateau, which of course is very distinctive for this CAR. Stem cell transplant consolidation for patients in remission following obe-cel did not appear to improve EFS or overall survival. However, ongoing CAR T cell persistence seems to be very important and it is certainly associated with improved event-free survival. So really to conclude, obe-cel could be considered as a standard of care for adult relapse for refractory Acute Lymphoblastic Leukemia. Now if we move on to Slide 23, it's really just to acknowledge everybody who's been involved in the conduct of this enormous study and in particular it's the patients, families, friends and caregivers; and of course all our colleagues, the study investigators and coordinators; and the health care staff of the study sites. So thank you very much for your attention and looking forward to the discussion.

Well, thanks a lot, Claire. It was a fantastic presentation. Let me just briefly look at the upcoming newsflow on Slide 25. As I mentioned in the introduction, we're obviously in the midst of the regulatory review process both in the U.S. and in Europe. The target PDUFA date that is November 16 at the end of the year. Also a key set of activities leading up to that event. From a data release perspective, we do expect obviously to update further at the EHA meeting, which is just about coming up within a week's time. And also in addition to the update you just followed and were going through with Claire, we'll be updating the impact of bridging therapy particularly with the focus on the impact of inotuzumab during bridging therapy as one of the additional data sets we'll be discussing at the EHA as well as look more closely at persistence and the sensitivity of detecting persistence and how that actually impacts the [indiscernible] in the patients as well, which will be a third part of the presentations that are planned for EHA. With regards to the regulatory process. In addition to the work that we do with the U.S. FDA, obviously there's more activity with the European agency EMA that will be ongoing during the course of the year. We also are expecting to file an application with the U.K. authority MHRA. And then finally, we obviously started also work in additional indications and are currently running dose confirmation study evaluations, which we expect to have initial data from by the end of the year. With that, I would like to stop here and actually open up for the Q&A.

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

So my first one is related to current practice. How common is transplant consolidation when giving CAR Ts to adult ALL patients?

Claire, do you want to take that?

Well, so I mean it is a really pertinent question and it's one of the biggest -- it's one of the hot topics in ALL. The decision is very easy. If someone's had a prior ALLO stem cell transplant because in a sense, a second transplant is something that we tend to sort of shy away from. So a lot of the patients that come through our clinic would have had a prior stem cell transplant and in that case we do tend to consider consolidation after CAR T with a second transplant because historically, the outcomes have been very poor from second transplant. For those patients who are transplant naive coming into CAR T cell therapy at the current time, essentially we cancel the patients who achieve remission after a CAR T about the watch-and-wait approach, i.e., just continuing to follow up some of the markers that Christian just mentioned such as B-cell aplasia, MRD and also CAR-T persistency. So we weigh up that approach versus the risks and benefits of progressing to consolidative stem cell transplant and it's very sort of physician dependent in terms of the approach taken. Our own practice at UCL tends to opt for a more watch-and-wait approach in patients, particularly those with ongoing CAR T cell persistency and those patients in unfunctional sort of B-cell aplasia and also those patients who've come in with lesser disease burden and patients who've come in with higher disease burden and in those patients who lose CAR T cell persistency. Then in those sort of situations, we would consider a consolidative allogeneic stem cell transplant. But certainly I don't think there's a sort of a uniformity and an agreed sort of paradigm that's followed across the field in adult ALL. I don't think people have agreed what is the optimal approach. But on the whole we tend to use the published information, which is patients with ongoing B-cell aplasia and patients who come in with lower disease burden. We use that as a sort of like a marker for sort of a better outcome post CAR-T. And so we tend to be more confident with the watch-and-wait approach in these particular patients. Christian, I don't know if you would add to that.

Yes. I think that probably what I would add is if you look at our field here is that I think that the key experience is that the only way that we could actually see a chance for long-term outcomes in the relapsed/refractory setting was actually a consolidation with transplant, whether this is with blinatumumab, whether it's with inotuzumab, whether it is also with a competitor CAR-T program. The statements when you look at it all across this is that you actually we try to get an MRD-negative state -- a complete remission with an MRD-negative state and then try to actually do a transplant particularly with the patient haven't been transplanted before as Claire was pointing out. So that's pretty much ingrained in the field in the sense that, that was one of the only ways you could get a longer-term outcome. I think what was unusual about the data that you just heard from Claire is that this is probably the first time that we see an outcome that did not get improved by consolidation of a transplant. And I think that was to us actually a remarkable part of -- when we ran the analysis, it was remarkable to see that indeed it does not improve. Now there's a logic to that and Claire pointed to that before, which is obviously that most of the patients that got transplanted in the study actually had ongoing persisting CAR T cells. Obe-cel was there and was still active. And by removing obe-cel through the preparation for the transplant, basically you lost the surveillance in these patients and now the transplant on its own obviously has a limited ability to do that over time. And we believe that, that actually led to this worsening of the outcome in actually the patients that did not get transplanted and had the benefit from ongoing persisting obe-cel in their system. So that I think is important. To my knowledge certainly -- and Claire correct me if I'm wrong there. But to my knowledge this is the first time that I think we see that indeed consolidation with a transplant post 1 of these targeted therapies actually led to certainly no improvement, potentially a worse outcome.

Yes, I think that's right. I don't think anyone has definitively shown that transplant is improving the outcome for patients after CAR T to date and certainly not in this analysis.

Okay. So maybe kind of following up on this and given the results that you've seen especially with patients who have more than 6 months cell persistence, do we envision a world in which transplant decisions are going to be made based on T cell persistence? Is this something you guys are going to start monitoring practically when giving obe-cel?

Yes. So I mean at the moment actually in the pediatric setting, there's a study ongoing which is using the combination of sort of the NGS-based MRD analysis of CAR T cell persistence trying to sort of develop almost like a sort of an algorithmic scoring system to be able to determine an individual risk at any given timepoint post CAR T to help guide these decisions because clearly these are really important decisions to get right. So we think it will be sort of systematic evaluation of the combination of parameters, CAR T probably plus a deep measurement of measurable residual disease to enable decision-making about consolidation or not in patients.

That's very helpful. And the last one, the abstract review yesterday was clearly very excited about the possible near-term addition of obe-cel, basically [indiscernible] that hopefully will be added soon. Is this the typical feedback you guys have been getting from physicians?

From every walk of clinical practice because not least of it is just so -- I mean it's been so easy to give in terms of the toxicity profile. It's the sort of drug that you would consider for your older comorbid patients. So in terms of the sort of, if you like, the burden to the patient; the burden to the patient family, the burden to the hospital unit associated with giving this; and then you've got these lovely sort of long-term outcomes by owning across the whole adult sector. Everybody is really excited, but the excitement also extends into the pediatric sector. So for instance sort of the investigators across the U.S. are really sort of pushing hard to enable access to obe-cel for their pediatric patients with ALL as well. So I think many people are watching the adult data with great excitement and imagining the use of it even more broadly. Christian, you probably would have something to add to that.

Yes. I think it's really resonating very well also in all the regional outboards that we have been running across the U.S. with physicians who have not been part of the FELIX study. The study does resonate remarkably well. It is a sort of a real world population that's represented in the data set including very challenging patients like patients with extramedullary disease and which certainly one with isolated tends not to be included in clinical studies. So there is a way to actually see the patients reflected in the data that the physicians are seeing in their own practice and I think that certainly has resonated a lot. The safety profile, as Claire said, is something that's immediately experienceable and has a huge impact on the hospital, has a huge impact on patients. And I think there is also a sense that [indiscernible] products that are actually easier to manage that you also have an ability frankly to treat more patients because the resources are not quite as strained that if you have a product that actually requires a lot of attention to be managed. So those are certainly feedbacks that we've been receiving and I think are very consistent with what Claire just walked us through.

And our next question comes from the line of Asthika with Truist.

I have a few if you don't mind so let me ask in a couple of clusters here. Dr. Roddie, I echo Gil's question here or a reflection that the discussion was very excited about this data. So I just want to ask you point blank. Is the sample and the strength of this data enough to be immediately practice changing? That's one. And then in the likely scenario where you have both obe-cel and Tecartus at your disposal, what is the use case for Tecartus? And then a third quick one here, if I can add to you, Dr. Roddie. In high tumor burden patients so the ones with greater than 75% blast, what else could you consider using to get similar results as obe-cel? And then Christian, I got a couple of quick ones for you too after.

Okay. All right. Claire, do you have them?

Well, so in terms of I mean is it practice changing with sort of immediate effect? I think the answer to that is yes. I mean this is the biggest study in adult ALL of CAR T therapy. I mean we treated 127 patients and I think these kind of couple of meier curves speak for themselves really. So I think in answer to that, yes and hence the excitement across the U.S. and the reception of the abstract yesterday. In terms of sort of decision making between products and again I think I've sort of voiced this on previous calls. It is to some extent like [indiscernible] and this is by far and away an easier to deliver product. It's associated with the long-term outcomes we've discussed in the slides. It opens up CAR T therapy to a whole new population of patients who you would never consider for [ Brexacel ], as I mentioned, those older and these comorbid patients. So it basically is giving an opportunity for therapy to patients who otherwise wouldn't be considered. So I think on those 2 fronts alone, it just is a massive, massive development in the adult ALL field. In terms of patients with more than 75% blast, again I mean obviously we've seen the data and we knew from across the board CAR T therapy and other therapies that these can be a difficult patient population to manage. And again it will be different depending on which physician you ask as to what approach one should take. I've certainly got patients in my practice who have more than 75% blast who have got durable long-term responses following obe-cel in the context of both Phase I and in the FELIX study. But there are other patients who have lost their responses. So I think we watch those patients very closely and we certainly consider if they are eligible potentially if they're ALLO naive, let's say, they would be the kind of patient who you would counsel about the pros and cons of watch and wait versus consolidation therapy. And that decision is heightened if for instance they lose their CAR T engraftment or they reconstitute their B cells. I mean I think that decision then becomes easier to make. But it's always a balance because the sort of head-to-head data of ALLO versus CAR T watch and wait is just not there and we're always sort of having to try and piece together the kind of retrospective data to sort of answer this question. It's never been prospectively studied. But yes, they are a higher risk group and we do watch them with great care and very closely. Christian, would you add to that?

I think that's right on. I think, Asthika, you had additional set of questions you were mentioning.

Yes. And Dr. Roddie, maybe if you just fine-tune on this question. Is there a use case for Tecartus if you have obe-cel at your disposal?

Sorry. Is there a what case for it did you say?

Like is there any type of patient that you'd say, yes, this is the kind of patient I would actually use Tecartus in over obe-cel?

If there is, I can't think of it right now.

Okay. That's really helpful. Christian, so I wanted to just check in with you on the persistence and efficacy that this data really links together quite nicely. One, how would you use this in your further development of obe-cel this knowledge that the persistence is now tied to efficacy? How do you use this in your further development of obe-cel in other indications as well as other CAR Ts at Autolus? And second, did you look at the evolution of the dominant clonotype of the CAR T cells over time? I'm wondering if this is dynamic or if there are any specific groups that persist and are potentially what's driving the long-term efficacy. And then if I can squeeze a quick question in on the autoimmune study. If you could give us an update on number of patients recruited, that would be great.

So first of all, I'll say the fact that persistence has a significant impact particularly in acute leukemia when it comes to longer-term outcome is obviously something that we knew about for a long period of time and actually were a deliberate property that we're looking to design into ode-cel. I mean the early information obviously that persistence matters particularly in pediatric patients came from the work that was done by UPenn in [indiscernible] that showed that indeed the case that have long-term outcome also have long-term persisting CAR-Ts. We then actually when we were doing the initial work with our colleagues at UCL in the CARPALL study obviously did see that also the children that actually have long-term outcome and got to cure also had long-term persisting CAR T cells and in that context, we did see CAR T cells measurable and actually could be followed by flow inward from these patients 3 to 4 years out. Now one of the things that you may remember that of those patients, we have the ability to actually analyze what the composition laws of those CAR T cells and what were features of the CAR T cells? And what was quite striking was that there was a bit more clone that was sort of surviving longer term with the CAR-Ts. In fact when we looked at those CAR T cells by flow analysis and looked at the various differentiation types of these CAR T cells, they actually looked pretty much in terms of composition of what the original product looked like that went into these children. So that's where we have actually a lot of information from the pediatric study we did a material work and part of that is published. So very much I think what we see is really that the property that actually encompasses all of those are trapped within our product and the product seems to be represented over time in a distribution [indiscernible] similar to what the original product looked like that was manufactured before and we analyzed before infusion. So those are kind of a few thoughts on persistence. Obviously we continue to work and we continue to follow these patients and I think there's a lot more that we will learn over time. As we sort of take a deep dive in the product cases versus outcomes and that's a key analysis that we're now actually going through and I think there's opportunity for additional updates as we go forward that look at those possibly also mechanistic type of relationships that we might actually find here. So there's still a lot to analyze. I think we have a good sense and we have been from the get go to the pediatric work on the importance of persistence and we start to learn with this very sizable data set our ability to really start to asking these much more multivariate type of questions for patterns, et cetera, that may actually impact outcomes. So that's an area of very active engagement and certainly we'll continue to do a lot of work in that area. And then the final part was you were asking about how we're doing on the SLE study. We did I think just a very recent call in Q1. Our recollection is that we told you that we had the first 2 patients enrolled and obviously very happy on that side and gave you an indication that we expect data from that study by the end of the year. There's nothing that's changed in that outlook.

And our next question comes from the line of Kelly with Jefferies.

I'm just curious in the 40% of the responders in the ongoing remission without transplant as a lot. The proportion of the high risk patients is similar to that outcomes?

Claire, do you have that?

In the guys with the 75% blast, was that the question or were they adequately represented in the 40% long-term responders?

Long-term responders that are high-risk patients in a similar proportion to that in outcomes?

So I mean I don't have that data to my fingertips, but obviously there were a higher proportion of those patients with the sort of over 75% blast who unfortunately did lose the response sort of at the earlier timepoints. So obviously we do recognize that the kind of that superior EFS curve, I think maybe Christian showed it earlier, that sort of correlates with the lower disease burden. You've got the difference when you subdivide it according to disease burden, you can see how that impacts EFS. So yes, proportionately I mean you are more likely -- I think that goes without saying, you are more likely to achieve the long-term remission in the sort of lower disease state. But I think that that's not unique. In this context, this is not unique to [indiscernible]. This is something that has been reliably sort of seen across all of the different CAR T cell therapies, tisa-cel in children and it's been seen R80001 in Spain. I mean it's just the paradigm, unfortunately, they're high disease burden. They'll convert that sort of slightly higher risk of losing response.

One element to add maybe, Kelly, is that in the slide deck, there are kind of the impact of tumor burden and lymphodepletion. So I think what we see is a reflection of that in the data. So it's not necessarily the tumor burden at inclusion that actually determines an outcome. But it's the tumor burden and lymphodepletion, which obviously gives you information about the nature of the disease, the progressiveness, the speed at which the disease actually progresses and your ability to influence that. That actually is kind of the information that you get at lymphodepletion because you had exposure then that more than 90% of the patients have been exposed to bridging therapy. So you actually get an information there that is actually very valuable. And as Claire was saying, there's obviously a buildup and obviously a weighting towards patients that have lower levels of tumor burden and lymphodepletion in that 40% bucket.

And the beauty of bridging, obviously I mean with the evolution in bridging practices, there is the potential for us to modulate the disease burden coming in. So we've had some degree of success with drugs like inotuzumab and sort of quite dramatically altering sort of disease burden between screening and lymphodepletion. So I think as we sort of become more knowledgeable in the space and I think we're going to be able to sort of improve burden and lymphodeplation in an increasing number of patients with better bridging practices.

And our next question comes from the line of Sebastiaan van der Schoot with Van Lanschot Kempen.

Congrats on another strong update. There was clearly a lot of excitement yesterday at the presentation. I am wondering whether you can provide some insight into the dynamics between loss of CAR T persistence, B-cell recovery and subsequent relapse. What are the time windows between those events? And if CAR T as well has had more of a gradual effect or is it immediate? And when would you then still consider to do a stem cell transplant?

Okay. Claire, do you want to take that?

So in terms of the -- I mean because again this is such an important sort of area of study in the field so we haven't formally reviewed all of data to present it yet sort of the chronology of these things and that will be the focus of sort of a subsequent update. But what we know from sort of the other settings, for instance [indiscernible] who looked at the NGS MRD evaluation in pediatrics because then it depends on how you're sort of measuring your disease regressions really. And so if you can get the sensitivity of detections on to sort of 10 to the minus 6 sort of reliably, then that's going to be particularly valuable data because it gives you sort of like an early snapshot potentially of someone who is inevitably going to relapse. So I think the modality by which you choose to look at your sort of disease burden is going to give us more opportunity to be able to salvage patients using the likes of MRD. But I think putting all of this together, putting all of these parameters together is going to be the focus of another update with those timelines. And Christian, is that fair to say? I think Michael is working on that data at the moment, isn't he?

Absolutely. One of the things that I think we can say is, Sebastiaan, obviously we do have a pretty good understanding of some of that dynamic from the Phase I experience both in the ALLCAR study. And I think what is fair to say is that we can see a sequence. The sequence tends to be a loss of persistence followed by recovery of B-cells and then leukemic relapse and I think that is a sequence that we see quite consistently. Timing is variable with that. But I think as a sequence, that is certainly something that I think we have seen. The only exception is when we actually have a patient that has a CD19 negative relapse. In that case, we could still actually have persistent CAR T cell without the relapse and the B cell is not coming back, but the relapse actually is starting to accrue. So that's the only exception to that. But in a CD19 positive relapse, we tend to see that sequence of loss of persistence, recovery of B cells and basically the leukemia coming back. But Claire is looking at that much more systematically across the data set work.

Okay. Can I ask more question? I think you mentioned that the prior implementation that we can remove CAR T cells. Is that only seen in a proportion of patients or is that in all patients who receive stem cell transplant?

Sorry, the conditioning therapy for the transplant ablates the CAR T cell engraftment? Is that the question?

Yes. Is that in all patients or in a proportion of patients?

Well, look, again that is also the focus of ongoing analysis at the minute. So we're looking at the impact on CAR T cell engraftment in the patients on this particular study who underwent subsequent ALLO transplant. But I mean the conditioning is super fine so ALLO transplant usually engage as sort of T cell depleting and chemo immunotherapies. So the experience across the field in CD19 CAR T is that it does ablate and the CAR T cell engraftment. But again within the FELIX study, that's a piece of analysis that's ongoing at the minute so to compare and to look at those patients who have those ALLO transplants and to look at the marking afterwards.

And our next question comes from the line of Matthew Phipps with Blair.

Congrats on update of continued durability and persistence there. I guess I'll ask about kind of commercial prep. Maybe you can just give us a little insight of how many centers you feel like you're kind of prepped and will be ready to go at launch and maybe just like cadence of expanding those centers in the U.S.? Also maybe when you can go to that second manufacturing subfacility, whatever you want to call it? And then lastly, any cadence on kind of care reimbursement and NTAP payments?

I think with regards to the preparation towards commercial launch, obviously this is an area of very heavy activity. There's obviously 1 key aspect of the activity what's going on at conferences like these conferences here at ASCO. In Chicago, which is really engaging with the treating physicians and really make sure there's a high degree of awareness to the program. There's a very intense medical sales program ongoing. The second area is really getting the centers ready to be in a position where once the product is approved can actually offer the product to patients. And one of the key things that obviously is important there is [indiscernible] have to be licensed to use CAR T cell products. That's quite an involved process and actually requires a very significant amount of engagement with the centers. The centers obviously need to go through some other aspects related to trading. There's aspects of how you manage the product once it's on the center, the physical handling of the product. But also the collection of longer-term data in the context of a REMS program, which are all components that obviously are relevant. In order to support all these activities including [indiscernible] support. In order to support that, there's a very significant level of IT support required. There are platforms that we're using that actually help with the orchestration of the product flow and making sure that there is visibility on where the products are and there's accountability at the centers of when to actually get the patients back in, prepare the patient for infusion and so on. So this is a very important process. There's also a lot of contracting work that is required because all of these aspects need to be tailored to the specific center. So typically you look at a time between about 6 and 12 months of work with each center where they are then ready and once the approval comes through can go to the final steps of activation. So we expect at the time of the PDUFA date that we should have somewhere in the range of 30 to 36 centers in a position where we could do the final step of activation once the approval is through. And then build very rapidly from that 36 center number up to about 60 centers that we expect to have as a key target to reach in the U.S. We would actually go on an almost continuous basis forward and really make sure that we actually get to that level in a relatively short period of time during the course of the first year of launch with the product. So that should put us in a position where we should be able to reach somewhere in the range of about 90% or have an ability to access about 90% of the patients that are treated at that stage of their disease in regress.

And our next question comes from the line of James Shin with Deutsche Bank.

Just wondering are preliminary rates for relapse and nonrelapse [ data ] available? And then for FELIX, is there a breakout for OS patients with and without prior blin exposure? And then Christian, the 30 to 36 centers that should be online. Is that just U.S.? Is there any EU facilities included in that number or no?

Claire, do you want to clear on the analysis?

So in terms of the treatment-related mortality on study, is that right? Because that was the subject of our prior sort of toxicity updates and as you're aware, obviously the immunotoxicity rates were really low and there is some sort of base preferability really low in fact, 2.5% or something like that level in patients. And there will be a couple of deaths on the whole study that were felt to be treatment related. So I think the TRM on study was actually really low. In terms of the blin versus no blin so again that's a piece of analysis we've got sort of like a team of statisticians looking at all of these different parameters that may impact upon outcomes. Obviously we looked at there was a [indiscernible] previously of people who've been previously exposed to blin versus not and there really wasn't a very marked sort of difference in kind of likelihood of achieving CR whether you'd have been preexposed blin or not, but we are conducting some analysis to look at sort of CD19 expression levels pretreatment based on prior blin exposure. So I don't think blin's coming out as being sort of like a massive sort of active -- it's not massively impacting upon your likelihood of achieving CR. I'm not sure was there another part of that question was for me or was it just the blin and the TRM?

I think those were the key questions.

Yes. The other question was for when Christian was mentioning the 30 to 36 centers. Did that include any European facilities?

No. Actually the focus obviously at this point is really on the U.S. launch and that's going to be the centers that [indiscernible] only. The approval in Europe is expected sometime during the course of next year. Obviously the process is somewhat different from the review process that the FDA runs. And would they actually allow us to initiate the launch in Europe? You have a country-by-country launch in Europe and we're in the process of actually running through the sequencing of the countries, et cetera. I'll provide more of an update at a later timepoint. But quite usual if we look at it at a launch sequence in Europe, it tends to start in Germany, France and the actual [indiscernible] and obviously one of the key areas for us obviously being a U.K. company is also to have a drive towards a U.K. approval and launch in the U.K. So both of those were hopeful that this can actually be happening through the course of next year while we're sort of ramping up the activities in the U.S. Now there's one question that Matt actually asked before that I didn't answer just before. One of the things that I think Matt asked was related to potentially having an NTAP which is a new technology access payment, which is basically an ability to support new therapies with options in disease settings for a subset of the patients that are supported by the U.S. government. That's a process that tends to be an annual process and so we certainly would expect that we would apply for an NTAP once [indiscernible] and that actually could provide an added level of support for the treating centers and that sort of an improved level of reimbursement for the treatment centers as part of that scheme. So that's just as a follow-up on Matt's I think second part of the question that I didn't answer before.

And our next question comes from the line of Yanan Zhu with Wells Fargo.

Wondering about in terms of the analysis for sensoring versus not sensoring the subsequent stem cell transplant patients. Has that kind of data and analysis also been done on Takata's ZUMA-3 study? If so, the outcome generally is similar or could a stem cell transplant have a differential impact following Takata's?

Well, to be fair, I mean the ZUMA-3 study, they were like 10 patients were consolidated with an ALLO transplant or received an ALLO transplant. That was 18% of all of the patients on that study and they showed that the median duration of response was similar. So I don't think that they saw like a massive benefit to consolidation with ALLO transplant either in that setting. So I'm not sure, Christian, if there's any other aspect that you would want to highlight there.

So when you look at the ZUMA publications, what we do see and what was highlighted there as well is that there was somewhat of an improvement. So there was not a big improvement because the number of patients that received the transplant was limited, but the curve was running somewhat better. So it brought the overall curve different obviously from what we are observing with our curve, with the transplant actually runs below the curve without a transplant. So there was a difference there. It wasn't huge because obviously the number of patients that got transplanted were very limited. But certainly some of the subanalysis that were shown over the last few years sort of indicated that at least there was a sense that these patients did better. And it was also I think probably reflected at the summary of the ROCA study that we presented at ASH at the end of last year where the presenter concluded that the recommendation was that the CAR T therapy should be consolidated with another therapy, one of which obviously would have been stem cell transplant. And similarly with the outcomes in sight of clearly long-term outcomes, the patients that actually were consolidated with stem cell transplant long term actually had a better outcome to the patients that did not get consolidated from an overall survival perspective. So there was a difference there that was visible and it was a bridge to transplant as one of the key uses of Blincyto similar to what I think Claire walked us through before in terms of general practice.

Got it. Then also I was curious about when using CAR T persistence as one of the parameters to predict outcome and intervene with stem cell transplant if necessary, I was wondering what might be the right timepoint. Looking at the graph you're showing for the 6 months, looks like patients could progress pretty quickly between 6 and 9 months, a substantial portion of the relapse happened during that 3 months. Do you think the 6 months persistence will still be timely enough to implement intervention to prevent those relapses?

Yes. I mean it's an interesting point, isn't it. It sort of comes back to the kind of question that was asked earlier as to what is the sort of the time interval between the kind of the loss of CAR T persistence to the recrudescence of your B-cell compartment to the sort of the relapse and I mean clearly the data is what it is. I mean there's clearly like an EFS benefit. If you've got ongoing persistence at month 6, but nothing is absolute and so there will be that sort of risk of patients sort of dropping off. It just depends on where you cut the curve and 6 months seems like a reasonable timepoint to do that. I think as we sort of move into the kind of field of the use of NGS methods of MRD detection, it will give us the opportunity if we do get those patients losing CAR T persistence. And then if we're using that test in conjunction with sort of like a deep and sensitive measure of MRD, we should be able to sort of make kind of consolidation decisions before the point of relapse in those patients as well. So I think the kind of the combination of measures is going to be what's going to be most potent in terms of helping us guide consolidation before patients frankly relapse.

I'm showing no further questions. So with that, I'll hand the call back over to Christian Itin for any closing remarks.

Well, thank you very much for joining, everybody. Really appreciate you taking the time. Particularly would like to thank Dr. Claire Roddie for joining us today and sharing her insights on the study and the treatment paradigms within this tough to treat indication. And we're looking forward to keeping you updated. So really appreciate your time today. Thanks a lot and have a great weekend.

Ladies and gentlemen, thank you for participating. This does conclude today's program and you may now disconnect.