Autolus Therapeutics plc (AUTL) Earnings Call Transcript & Summary

Okay. With that, I guess we'll get started. Good morning, everyone. My name is Noah Eisenberg. I'm a biotech research associated with JPMorgan. It is my pleasure to introduce our next company -- presenting company, Autolus. Presenting on behalf of the company is CEO, Christian Itin. After the presentation, there will be a Q&A session. [Operator Instructions]. So with that, I'll hand it over to Christian.

Thank you very much, and welcome, everybody. And first off, congratulations. You made it to Thursday at the JPMorgan conference. So that's an accomplishment in its own right. So great to see you all. And frankly, thanks for joining this late presentation and the schedule. I'll be introducing you and walking you through where we are and where we stand with the -- our programs. We're developing CAR T therapies. And obviously, we're a listed company, and please look at our SEC filings for the risk factors that are relevant for the company. We're building an integrated CAR T company, and we're actually very much down the line in actually accomplishing this goal. First off, our lead program, obe-cel, just read out the primary endpoint in the pivotal study, which gave us a lot of confidence around the program. I'll actually introduce you to the data that we just announced. The indication that we're active in our patients with acute lymphoblastic leukemia, a focus on the adult patient population, which obviously have a very poor outlook. And we're starting to see very remarkable data, and I'll be walking you through that. We're also exploring the activity of the product in the Hodgkin's indications. I'll give you a flavor of that, but I think there's significant opportunity for the program to be expanded beyond ALL into an additional indication set as we progress. The pipeline is really built on a suite of technologies that we developed over the last few years to allow us to really tailor the properties of our products, and I'll walk you through some of those technology elements because they also led to some of the deals that we have announced more recently and are relevant in that context. What is really important in our field is the ability to supply product. This is a personalized therapy. And the ability to actually deliver for every and each one of the patients is absolutely necessary, and it is essential. So what we've built up is a very significant level of capability. We've obviously, just as I said, completed a pivotal study. We dosed all the patients. We've done it through the pandemic. And this obviously was very challenging from a supply perspective. We managed to deliver product to all our patients, do this successfully and navigate all the various challenges that were coming up on logistics and many other aspects. The manufacturing setup that we're using for the commercial supply of the product is coming from a manufacturing facility located in the U.K. Also our clinical trial supplies come from the U.K. and is designed to allow us to capture about 2/3 of the total market opportunity, both in the U.S. and in Europe. So we will, out of the gate, have an ability to actually serve the market. This is very different from what we're seeing with the CAR T programs that have fantastic data in DLBCL, fantastic data in multiple myeloma. But obviously are dealing with much, much bigger indications and are really difficult to catch up with the demand and actually fulfill the need that is currently out there. And I think any one of you that actually has relatives or friends trying to get access to these therapies today, do know that this is an incredibly difficult thing to do. And many people, even as well connected as we may be in here, are not capable of getting access. So we're going to be in a very, very different position because, out of the gate, we'll have the capability to deliver the product at the scale required. Now we've set up a set of collaborations. An important 1 we closed at the end of 2021 with Blackstone Life Sciences, a collaboration that includes a total value of $250 million, of which $220 million are actually already paid into the company, and they were part equity and part program financing for the LEAP program, obe-cel. We also established technology collaborations with Moderna and BMS. I'll briefly talk about that later on as well. And there's obviously quite a bit of opportunity for additional collaborations going forward. Now this is a business where you have to -- we're at the stage where we are, where we're obviously having a readout on the pivotal study. We're driving towards a BLA filing and have to get ready for commercialization, where you have to be able to fund your activities. So having a strong cash balance is important. We did raise some additional capital at the end of last year as well as received a $70 million non-diluted funding element out of the $250 million collaboration with Blackstone in the same period of time. So we ended the year with about $380 million in cash, which is important and allows us to really drive to the key regulatory steps, the filing as well as through the approval process in the U.S. and Europe. So with that, I'd like to focus first on the obe-cel program. And remember, this is a program designed to see the CD19 structure on leukemias and lymphomas. And this is a quick summary on some of the key features. So first of all, the program actually -- okay. I don't think there's much I can do about that, I'm afraid. They're in display mode here, but I appreciate you're mentioning it. The slides are not showing on the screens. All right. So thank you very much, actually, for pointing it out, because obviously there is no visibility from where I'm sitting here or standing. So the program that we're running here is really designed in a very different way from the conventional CAR T programs. And what we were looking to do is create a product that engages the target cell like a normal T cell would engage it, which is relatively short. And with that, you have a high level of activity allows the T cell to recycle quickly and you avoid overactivation of the T cells, the CAR T cells. And as a consequence, you have less cytokine release, less toxicity, but you also have an ability to actually get a product that expands more into patients and actually persists longer in those patients with -- is a key feature to get to long-term remissions. What was very unusual with the program was not only that we obviously see high initial rates of activity, but we do see sustained activity in these patients. So we have now data that go out -- is going out to 4 years in follow-up, and we're seeing that patients are in continued, complete remission without the need of any additional therapy. Now the reference point is that these patients normally do pass away within less than a year. So this is a very unusual outcome that we're seeing and something that we couldn't actually see in our field before. All those patients that actually have these long effects, as you can see in the middle, in the swim plot, the green lines, all of them have persistent CAR T cells up to 4 years. So it's a very unusual property. It goes back to the fact that this product has -- behaves very much like a normal T cell, and with that actually gives us a very unusual level of activity. When we look at the development path that we're going through, obviously where we're looking to get preferred access to all the key regulators for the program, we have orphan drug designations in Europe and the U.S. And then an RMAT designation with the FDA, a prime designation with EMA and an ILAP designation with the MHRA. I mentioned the unique mechanism of action. What's fundamentally different about our product is that it has an ability to engage rapidly with the target, which gives you specificity, but then also can disengage rapidly, which is a very unusual property to screen for and which makes it completely different from any of the other products that actually have developed -- been developed in our space and all products that are on the market. In fact, all commercial products are identical in their way on how they engage the target structure on CD19. And this is also the reason why they do share a lot of the challenges on safety as well as some of the other challenges related to lack of persistence that we're seeing with many of the programs. Now we just completed the enrollment and dosing of a pivotal study. The study name is FELIX. We conducted this study in 34 centers; 24 centers in the U.S., 7 centers in the U.K., 3 centers in Spain. The study was conducted throughout the pandemic, which meant that, obviously, we did not have access to the centers. We couldn't go there. And obviously, the patient population that we're dealing with here are highly immunosuppressed. So you can imagine this is about as difficult population to work with, particularly in an environment where there is high risk of infection. And indeed, we did lose patients to COVID, as you would imagine. Now I'm mentioning this because normally when you develop in a patient population like this, you're all over the study. You're going to be at the centers, you're going to make sure you really control the study to the highest degree possible. Now we find ourselves in a situation that we couldn't do any of that. That is important as we're thinking about what the data actually comes out of this study. So it's very -- it was a very challenging environment. It's also challenging, of course, from a logistics perspective and so on. We were able to deliver this study on time and on quality. Now when we look at the overall outcome, first of all, we've presented a first look at the data, which is an interim analysis at the end of last year. We looked at the first 50 out of 90 patients dosed that had reached 3 months at least in terms of follow-up. And what we're looking at is the overall response rate, which is based on complete remissions and so-called complete remissions with incomplete hematological recovery of CRis. So both of them from a leukemia perspective are patients that have no leukemia left in their bone marrow and elsewhere in the body. What we do see is that we hit an overall response rate of 70%, and we do have an excellent safety profile. I'll walk you through that in more detail on the next slide. What we do have here, I think, is on the right side of the slide here, some of the safety data. This data set actually was based on 92 patients. So this is a very mature data set. And we have shown that, in fact, patients with high-grade cytokine release less than 3%, patients with high-grade neurotoxicity, all fully reversible, less than 8%. And we have less than 25% of patients had any form of neurotoxicity, a very unusual profile in this patient population. And what we also did announce at the end of last year that the quality of the data triggered and triggered early a milestone from Blackstone under our agreement of $35 million that was triggered at -- in the end of November, early December. Now one of the things that it gives us an enormous amount of confidence around the program is not only that the FELIX study actually turns out really well, but also that the data that we've been seeing across all studies conducted with the program are remarkably consistent. If we go from the left-hand side, the CARPALL study was a pediatric study. So these are children. Typically, you treat them at lower tumor burden because you need to get them very early on. The second study, the ALLCAR study, are adult patients that were treated in the U.K. before the pandemic. The FELIX 1B study was the running into the pivotal study that was already in the pandemic with most of the centers in the U.S. And then the pivotal study, obviously, with the large proportion of the centers in the U.S. And what you can see is that we have a remarkable consistency around the safety profile as well as the overall activity profile. One of the things that we did observe in the pivotal study is, and this is not a surprise when you think about the pandemic background, is that we have more patients that had disease that had evolved from not only disease in the bone marrow, but evolved to actually take hold in other parts and other organs and successfully grow there, so-called extramedullary disease. And in fact, what's known about those patients is that they're very poorly responding to therapy. And in fact, if we were to correct and just look at the patients that have no extramedullary disease, arrowed levels of activity are absolutely smack on where ALLCAR19 was tracking before. So it gives you a sense for the robustness of the data, but also the real-world character of the data that we've actually generated here, not voluntarily but as a matter of fact. So when we then look into kind of the outcome, and this is really where we have the long-term observation, this is now from the ALLCAR study where we, as I mentioned, up to 4 years of follow-up, this is really what makes the program very unusual. Clinical benefit in these patients is the ability to convert patients into complete remission and sustain them over time with any additional need of therapy. As you can see, we go bottom up. Obviously, we had some patients that did not respond. Then we had some patients that responded but relapsed quickly. So the yellow circles are patients that relapsed with so-called CD19-negative disease. So in essence, the leukemia became invisible to the therapy by losing the very structure the therapy was designed to recognize. If you then go a little further up, you see 3 red circles. Those are patients that relapsed actually because the CAR T cells, the obe-cel product didn't persist long enough. The cells petered out, and then you actually have disease coming back that had CD19 on its surface, and the patients were relapsing. Above those, you see a group of patients that are in long-term remission between 2 and 4 years without any additional therapy. 35%, there is a second from the top at a transplant. But everybody else, the 7% out of 20% to 35% have nothing else, and they're in continued remission. Every single one of these patients has persistent CAR T cells. This is a very unusual property, and you haven't seen any of that with any other program reported to date. So it gives us hope that indeed we can get a transformational outcome for these patients, which frankly was the hope that we had when I developed with my old company, Blincyto, the current leading program in the space, we could never get that. This is very different. Now when we look at the standard of care, and I mentioned Blincyto before, which is a T cell engaging CD19 targeted monoclonal antibody -- bispecific antibody that is being marketed by Amgen, developed as I mentioned by my old team when I ran Micromet, has a very attractive profile. And when you look at the safety, it has a very good safety profile similar to what I just told you that obe-cel has. The difference is neurotox of any grade in these patients is 65%. What we're seeing with obe-cel is less than 25%. This matters because you don't know when a patient has neurotoxicity, whether that patient develops a significant form of the adverse event or whether it's just the passing event. So we have a remarkable outcome here compared to Blincyto. And obviously, when it comes to efficacy, we're beating Blincyto hands down on every aspect of efficacy, most importantly, in long-term outcome. Besponsa is used as a bridging therapy, can induce responses, cannot hold responses. And it's used as a bridge to transplant or bridge to another therapy. So you could never actually get a stronghold in this indication. And then we have Kite-Gilead's Tecartus program, which is the first approved product in adult ALL. And as you can see, the product has a high level of activity, but it comes with a very significant level of toxicity, where you have 26% of the patients with high-grade cytokine release syndrome, 87% with neurotox, 35% with high-grade neurotox and 40% of the patients on vasopressors. So give or take, half of the patients end up in the ICU to be managed. That does not happen with obe-cel. So when we're looking at kind of the opportunity, the medical need, actually the medical need hasn't changed much as much as I would hope to have said that it did after we got Blincyto on to the market. We bought time with that product, but we didn't change the outcome. We still have about 3,000 patients that are in need, relapsed/refractory setting end stage of the disease between the U.S., Europe and Japan. When we look at the opportunities here, obviously, it's clearly the focus has to be on a therapy that gives you a long-term outcome, which is sort of the key parameter that you have to go for. Now in order to understand actually what that medical need is and what you can do with the program in this indication that actually is suitable for a large part of the patients, we can look at Blincyto. Blincyto will be, at the end of 2022, above $500 million in sales. When we look at the program, what that means is that approximately 2/3 of the patients do receive Blincyto today. And when you look at the cost of the therapy, it's about around $100,000 per 4-week cycle. Most patients get up -- the median of the patients get about 2 cycles. And if you treat patients that have lower disease burden, you will be able to actually give them a third, maybe a fourth cycle therapy, a therapy at which point the cost of therapy are very close to identical actually what we're seeing on the CAR T side. What is important, though, in terms of what enabled Blincyto to reach that number of patients is the safety profile and the fact that the product can actually be managed not only in an academic center but also in non-academic hospitals. And we believe with the safety profile that we have and obviously much less complexity in delivery because it's a one-off therapy, it's not -- sorry, a continuous IV infusion, that you have to actually give over 4-week cycles for an extended period of time with Blincyto. We believe we're very well positioned to actually be able to capture that opportunity with our product. In terms of price, the prices in the CAR T space, in ALL are between about $450,000 to about $500,000 in the U.S. In Europe, about 10% reduction of that price. So when we look at the steps forward, first of all, we're planning to have the full data at ASCO, middle of this year, and also another one at the day at EHA. So that's going to be in the June time frame. We then will have long-term follow-up plan for ASH. We're targeting the BLA filing for the program towards the end of this year, the EMA-MAA filing in -- towards the end of the first quarter, 2024. And the U.K. filing in the second quarter 2024. So that sets us up very nicely for the key territories that we expect to be initially active in. Manufacturing, obviously critical, is that your commercial manufacturing site has to be fully validated and demonstrated its full level of activity and consistency. That work is currently ongoing. The facility actually was ready at the end of last year. We could take over the first clean room, started that validation work. In the next 6 to 7 months, this is going to be a key focus to get the commercial facility fully validated. And this is not a nice PowerPoint slide. This is a real reality with brick-and-mortar and actual facility. When we look into the commercial side, the critical things that we need to focus on this year, on the one hand, is medical affairs. It's the awareness around the program. Secondly, it's the HTA dossiers. It's the value proposition for the payers, which is really critical to pull together. And the third area is the center onboarding. Centers take about 12 to 15 months to be ready to be able to deliver commercial CAR T product. And a lot of that time actually comes from contracting. Obviously, you have to have product handling, the handling of the patients, but also you need reimbursement support, you need other services at the center, et cetera. So it's a bespoke approach for each one of the centers and to sort of make sure the center is in a position to actually deliver product to patients. So that starts middle of this year. And obviously, it's a key activity to be ready. Now moving to sort of the broader opportunity that we see with obe-cel. We've been doing quite a bit of work. This is on the right-hand side in non-Hodgkin's lymphoma as well as in chronic lymphoblastic leukemia. And we start to see remarkable levels of metabolic CRs across the non-Hodgkin's indications. We also see very nice levels of activity in CLL, including patients obviously reaching molecular clearance of the disease in the marrow in all responding patients in CLL as well. The safety profile is remarkable, a remarkable safety profile from CRS and ICANS perspective, and I think will bode very well for this program and the positioning of this program in this space. So we're exploring the opportunities here. There's a number of options. I think we have particularly attractive opportunities in the more aggressive forms of the disease, again, where you have a chance to get long-term remissions and transformational outcomes. Now in terms of the life cycle, we started to work on sort of the next version of obe-cel which we call AUTO1/22. And what we're looking to address is the problem that we picked up in the pediatric patients. Most of the cases that did relapse, relapsed because they lost the CD19 structure on the surface of the leukemia. And so in order to make it very difficult for the leukemia cells to evade recognition were actually engineered a second chimeric antigen receptor into our product, which is very potently recognizing and attacking cells that express CD22, so second structure on the surface. And we tested this initially in kids that were not eligible for Kymriah, which is the standard of care. Kymriah is Novartis' CAR T program, highly active, true standard of care in pediatric patients. But if you already have been on Kymriah and failed, you cannot go back on, at least not in the U.K. And if you had extramedullary disease, you also would be excluded from getting on Kymriah. So we have basically a group of patients that are true end stage, cannot actually get access to CAR T. And when we look at the activity we would have expected for obe-cel in those kids at Kymriah, it's about 40% overall response rate. We're coming in at 83% with our product. So we have a very high level of activity, very good safety profile again. And it tees us up very nicely as sort of a part of the life cycle with the iteration of the program. And we're currently looking at the timing on when to take that program into further steps, development steps. But we can choose the timing on this program to some extent. And we'll balance it with an expansion of the indications for obe-cel in terms of the order at which we're going to do that. Now just a word on the pipeline. I mentioned the fact that we have a modular approach to sort of programming the cells, and we do that with protein modules that change the behavior of the cell. Obviously, one behavior is -- one is the recognition of structures on the surface, that's the targeting element. But there are also basically the way for the sales to adapt to difficult environment, a hostile environment. And we're using for that modules that actually rendering the cells insensitive to checkpoints, an area of a lot of focus in Oncology. TGF beta is another example, but also give the cells a survival support in that hostile environment as well. So quite a bit of technology there. I do mention that not only because we introduced in our own programs, but it also -- it's been the basis to act for the collaboration that we have in place with Moderna and with BMS, which are actually around particular aspects of the technologies that we have developed. Now when we look at the early stage pipeline, we got the AUTO4 program, AUTO5 program targeting T-cell lymphoma. Unique challenge, very difficult to target that lymphoma without actually rendering the cells aplastic for T cells, which is not compatible with life as my CSO convinces me every time when we have that conversation. And then when it comes to solid tumors, we're also starting now a program with a very sophisticated cell program in neuroblastoma as well as a multi myeloma program that we currently have active with our collaborators at UCL. Now the program in T cell lymphoma, again, very high medical need. In fact, when you look at the NCCN guidelines, it basically says once you're through the frontline therapy is go -- and you relapse, go on a clinical trial. That's not an endorsement of the standard of care. It's a really difficult situation. And so it is a very high medical need setting, quite similar to what we're seeing in acute leukemia. Now what we're starting to see with AUTO4 as we're dose escalating growing bottom up from low doses to higher doses, we start to get these green lines. Again, as seen before, those are, in fact, metabolic complete remissions. And we're starting to see meaningful 9 to 12 months follow-up in these patients sustained in metabolic remissions, which is really encouraging because it tells us that we're safe. We have an ability to hit the T cell lymphoma, and we're not actually impacting the overall T cell compartment, which was the other part of that equation. Now we're currently optimizing the manufacturing process, and we're actually retesting in a few additional patients. And I think with that, we'll have a very good view of the overall profile of the program. And with that, have an ability to take it forward. The sister program, AUTO5 is a late IND-stage enabling studies, and we are certainly looking at this program also as an opportunity for potentially [ A ] partnering around it. Now manufacturing, I mentioned before, the importance, obviously, here is when you deliver a personalized medicine, it is personal. You have to deliver for every patient that you actually take on to your product. And you have to make sure that you can do this consistently with consistent quality, and you have to be able to match the demand as we talked about at the onset of the conversation here. What we're looking at here in the middle is a picture of the build of the facility that was in September where we're lifting the HVAC units on top of the facility. As an aside, this is a complete modular buildup here, fabricated to about 90% off-site. We did this whole project from breaking ground to actually taking over the first clean room in 12 months and 2 weeks. So it's a very unusual build, and we did a modular buildup also thinking about the potential for adding additional facilities over time in other jurisdictions. So it gives us the scope with regards to 2,000 patients, what currently is being reached in this indication with Blincyto, about 60% of the opportunity. And we believe that actually sets us up very well for a successful launch of the product. We're in the process of manufacturing or putting together the key data for the BLA submission. And the way we do manufacture is with a fully enclosed manufacturing process. We're operating with Miltenyi Prodigy machines, been working with Miltenyi for probably close to 7 years now and are making sure that we can use as much automation as possible in the process. What this allows us to do is actually manufacture this product with a very attractive cost of goods, which has been one of the other issues that we have in the space. We expect our cost of goods to be in the range of about 15% at the -- as we started getting this product to market. So this is not only very active, but it's also economically sensible with a reasonable level of profitability. And I think that is not -- has been certainly a challenge across the field, so it takes a lot of attention to that particular topic, and that's what we've done. These numbers are fully loaded by the way, with the full knowledge of the cost of the facility as well as all depreciation and so on and so forth. Now just finally, obviously we've added quite a bit of cash towards the end of last year. We did a public offering, had some cash coming back from the tax services in the U.K. and also $70 million from 2 milestones, received from Blackstone. One was obviously related to the achievement of the pivotal study endpoints, but the second one was actually related to manufacturing progress, which is very critical as we just went through and got triggered by key data that we generated in that process. And then finally, obviously, we think we have an interesting year ahead of us. Obviously, focus is really to get obe-cel into the regulatory process with key data releases planned for middle of the year as well as the end of the year. And filing -- first filing towards the end of the year, and then additional filings in Europe in the first half of next year. We expect to provide updates on the pipeline programs with additional data and follow-up, and obviously have quite a bit of opportunity to sort of actually continue in ability and our setup for collaborations as well. And I do mention the manufacturing topics as well and getting ready for the commercialization. And so with that, I think we're in a very interesting point with the company. We got the cash to deliver a very significant value step. We've got the data to know that we have a differentiated profile of a product that goes -- addresses a high medical need with limited competition and with possibly a transformational outcome. And so with that, happy to take questions. Thank you.

Great. [Operator Instructions] But to start, you mentioned that in the FELIX study, there was a disproportionate amount of enrollment of patients with extramedullary disease. What makes these patients less likely to respond to therapy?

In essence, first of all, it's a higher amount of those patients, not disproportionate because that would suggest it's like half. That's not what it is. But it's a substantial amount of the patients. What makes the disease more difficult to treat is that it's basically an evolution of the disease. And you can think of it as like a gain of function, because the normal location for this disease is in the bone marrow. That's where the cells reside. That's where they grow. That's where they outcompete and, frankly, inhibit the activity of the immune system to regenerate in the marrow. And with that gain of function, the cells actually change in terms of the phenotype. They're able to migrate to other places in the body and then grow. And in that other environment, not in the bone marrow, the cells are more difficult to get to. And because they basically learn a few more tricks actually are a bit more difficult to handle. Typically, what we're seeing across the board is about a 50% reduction in overall response rate in patients that have extramedullary disease. It's a real kind of challenge to actually tackle those, that stage of disease.

And what is the background rate of patients with extramedullary disease?

It's relatively low, and it's in a way you can think about it, it's -- you select out these patients. Because either if you have a very rapid progressing disease and you don't have much intervention, the patient basically dies, typically of infection, often sepsis. And obviously, the more you can basically keep the patient alive, if you start selecting out more advanced stages of the disease, and that's basically what we're starting to pick up. So it's been reported as an example, as a challenge for patients that have been on Blincyto and many of the patients post-Blincyto do actually relapse with extramedullary disease, and that's been a huge issue for the physicians to sort of handle the patients at that stage.

Congrats on the data. One of your slides mentioned for partner for commercialization of obe-cel. You're considering EU partnering? Can you speak a bit more to that? And what commercialization activities you're planning to do yourself versus partnering?

Right. So on the commercial side, the current focus that we have, primary focus is to commercialize the product in the U.S. We're setting ourselves up to be in a position to commercialize in Europe, but I think we're open to consider partnership in Europe. Obviously, we're supplying the product, but we would definitely be open for a conversation. And this has a lot to do with just managing complexity as per sort of going through the process. As you can imagine, there's a lot of heavy lifting as you're setting up the infrastructure for this type of therapy. And so in that regard, I think that's certainly a conversation that we can have.

What feedback have you gotten from physicians regarding the CRS and ICANS in their decision to employ CAR T over other options in ALL?

Well, it starts with the -- I think the realization that unfortunately for these patients, you're pretty much out of options. You can put them on Blincyto, they will fail eventually. At that point, you're typically very close to palliative care. And in fact, today, you could use Tecartus still in these patients. But because they're very frail, that's not an easy decision, particularly if you see the adverse event profile and the limited long-term benefit that I think so far has been established. So it's a very difficult environment, I think there, and there's a very, very high medical need. Having a product, particularly in these patients that are not doing well that is well manageable is really important. And then obviously, from an overall perspective, actually having a chance of a long-term outcome is all you'll be looking for at that stage. And clearly, putting the program into an earlier line, which is activities that we're active in, including treating patients with minimal residual disease, that is obviously the optimal place to actually place the product, and that's how you will maximize positive outcomes for patients. Unfortunately, there is not an awful lot of options left at that point. These patients tend to have gone through stem cell transplant, failed many of them. And those that didn't get a stem cell transplant actually are not in a position to actually take one because of the toxicity. And getting a second transplant that has sort of a treatment-related mortality that's up to 40%. So it's a very, very difficult choice. And Europe typically isn't done, but also in the U.S. mostly isn't done.

So you just made -- so you're enrolling both on morphological and an MRD cohort with obe-cel. Could you just give us some color behind the strategic rationale of the MRD cohort?

Right, happy to do that. So one of the challenges we have in the field is that the regulators require us at this point still to actually wait for patients to have a certain amount of disease burden in the marrow, before you can actually include them in the trial. And this is called morphological disease. It requires you to have 5% disease burden in the marrow. Now the reality is that, we all know in the field is that these cells all come from a single clone, and that's just a single cell growing, growing, growing further. And so -- the field has over the last 25 years developed obviously methodologies to actually pick up a clone that starts to grow very, very early. And that's initially done by flow cytometry, then was done by PCR. Now it's done by NGS by sequencing. The sensitivity instead of 5% is 1 in 1,000, 1 in 10,000, 1 in 100,000. When, as a physician, you see that signal come up, that's the point where you actually start treating. You do not wait until that patient gets worse and has 5% tumor burden before you start treating. So what we have is sort of a situation where we have a disconnect between what's required to get regulatory approval and what clinical practice is. And so what we're looking to do is that we're generating data to actually also support the physicians in their own decision-making to actually utilize the product at a lower level of disease burden, which is frankly, the right thing to do. And it's straight rational when you think about what the disease is, how it works. And when you look at, in particular, the pediatric situation where the disease is also quite explosive in its growth is that there was an approval for Kymriah in morphological disease. But today, the physicians are treating the kids all when they actually are in the MRD, minimal residual disease, low tumor burden because it gives you more time to actually fight the disease, and it gives you a much better chance to win because there are less cells to get rid of. So it's a probability game. The more cells you have to get rid of, the more likely that is you're going to miss the one that ultimately will kill you. And that's really what this is about. So what we're doing with that additional work is to actually make sure there is data to support the use at a somewhat earlier stage of the recurrence.

And then is there -- from the regulatory feedback you're getting, is there a potential to include the MRD patient data in a product label?

I think there is probably one downstream. I mean it took quite a bit of time. We developed this strategy when we developed Blincyto, and it took quite an extensive amount of time for that knowledge to be actually included into the label, a bit quicker in Europe actually than it was in the U.S. What we want to do is here is really provide the information for the physicians to actually make their decisions. And then obviously downstream, we expect to actually use this kind of an approach in an early line of therapy where this is going to be particularly important.

Could you give an enrollment update on the MRD cohort?

I think we're just about being caught.

Well, thank you.

Thank you very much for questions.