Autolus Therapeutics plc (AUTL) Earnings Call Transcript & Summary

Hello, ladies and gentlemen. I am pleased to welcome you to Autolus Therapeutics ASH 2022 Investor Conference Call. As a reminder, this conference call is being recorded. I would now like to turn the conference call over to your host, Olivia Manser, Director, Investor Relations. Please go ahead.

Thanks, Justin. Hi, everyone, good afternoon or good morning, and thanks for joining us and taking part in today's call, in which we'll be covering the data we're presenting at the ASH conference. So this is Olivia. On the call, as usual, are Dr. Christian Itin, our Chief Executive Officer; and Dr. Lucinda Crabtree, our Chief Financial Officer. So before we begin, as always, just to remind you that during today's call, our discussion will contain forward-looking statements and those are on Slide 2. So please make sure you're familiar with the disclaimer slide. And with that, I'll hand over to Christian to summarize the data. And afterwards, we will welcome your questions. So over to you, Christian.

Well, thanks a lot, Olivia, and welcome, everybody, for joining this morning. Really appreciate you taking the time and obviously, a number of very eventful days for us at the company with a lot of very positive progress across the board. We'll talk briefly about the FELIX Phase II outcome of the pivotal trial, the interim analysis, where we were able to show that we met the primary endpoint. We'll then look into the clinical data updates that we're running at ASH. I would say my key presentation yesterday looking at long-term follow-up on our B-ALL patients as well as longer-term follow-up on the non-Hodgkin's lymphoma and CLL cohort that we continue to work on. And then an additional follow-up with our 2 programs, AUTO1/22 dual targeting approach in pediatric ALL and AUTO4 in peripheral T-Cell lymphoma. We also will mention our recent corporate updates. Obviously, we have taken out our first clean room in our commercial manufacturing facility, which was actually set up in record time. We had 12 months and 2 weeks from groundbreaking to actually starting to move in and starting operating within the facility, which certainly is a record time. When we then obviously announced also the accelerated payments of 2 milestones on the Blackstone agreement due to the progress, both in the clinical as well as the manufacturing side of the business related to obe-cel. And then we obviously did announce also at the end of last week, $150 million offering, which we expect to close early this week. The expected cash runway with those additional events happening is extended into 2025. Now moving to Slide #5. As you all remember, obe-cel, obviously, is a product with a very nice differentiated mechanism of action. We've generated a product here that engages the T cells -- engages to target cells in a physiological way as possible, gives us a high level of activity but avoids the overactivation of the CAR T cells and all of that is really driven by the binder that we're using, which gives us a fast on-rate but also a fast off-rate from the leukemic cell once the kill actually has been delivered. Gives us a unique set of properties. Obviously, you're well aware of those related to the remarkable persistence and the improved safety profile and overall, obviously, a very high level of clinical activity that we have been able to see across a range of indications. Now focusing on ALL, just on Slide 6. Obviously, the opportunity here remains very high. We've obviously seen a lot of progress over the last few years with the introduction of Blincyto, which is now obviously clearly the standard of care in this therapeutic setting. However, all of these patients, while gaining some time still in need of therapeutic intervention, and in that sense, the market actually hasn't changed in terms of this size. And we're also, obviously, in the course of last year and into this year has seen Tecartus to be launched both in the U.S. as well as in Europe as the first CAR T program for this patient group. Now when we go on to Slide #7, a quick summary of our pivotal study that we're conducting with obe-cel. The FELIX study is designed to generate a data set in the patient population that's so-called morphological disease. These are patients with more than 5% tumor burden. And the primary endpoint is based on the achievement of complete remissions that can come in 2 flavors in ALL, either complete remissions with full recovery of neutrophils and platelets, these are conventional CRs, or complete remissions where there is an incomplete recovery of neutrophils and platelets, which are CRis. So the primary endpoint, actually, looks at both of those types of complete remissions and forms obviously the key readout for the study. Secondary readouts obviously then include the MRD negativity rate in those patients, event-free survival and duration of response. As you remember, there is a second arm to this study, which is not part of the registration data set per se, which are -- is including patients that have lower disease burden, so-called minimal residual disease, which is tractorized, the disease that's less than 5% disease burden in the marrow. And the patients that we're enrolling there are really designed to give us information about the product properties in that patient group, which is more and more the stage at which -- of the relapse at which physicians want to intervent and do intervene in terms of the therapeutic activities. All of this obviously is designed to then give us a broad range of data across the entire range of disease burden in the relapsed/refractory setting, which should support obviously the use of the program once it is approved and on the market. Now on Slide #8, we're looking at the sort of top line outcome of the FELIX study. The first data that we have now reported on the efficacy side is based on a prespecified interim analysis based on 50 patients. The data are based and reviewed by an independent data monitoring committee and is looking first at the overall response rate, the primary endpoint index group. We have demonstrated that the product achieved 70% overall response rate in these 50 patients. And what is important when we look at the background of the patients, we see that we have a highly comparable characteristics with the patients based on -- compared to our FELIX 1B, our running study that we have conducted, but also compared to the competitive programs in the space. What is different, though, is that we do have a higher percentage of patients that have so-called extramedullary disease. Actually, the extramedullary disease is, in essence, leukemia that has managed to -- actually, as a gain of function, managed to escape from the bone marrow and cell elsewhere in tissue and actually, start propagating outside of the bone marrow. What's known about these patients is that they tend to actually very poorly respond to therapy. And indeed, if we do, actually, an adjustment for the difference in the numbers in patients with extramedullary disease, we do see that we get, actually, an overall response rate that very closely match what we had seen in the original ALLCAR19 study. Now what was very important when we think about the time that we actually conducted this study, and this was obviously during the peak of the pandemic. And whenever you run studies with highly immunocompromised patients that are very fragile and with a lot of comorbidities, in any normal situation, you'll be very close to the trial site, you'll be very close to the patients, you'll be present at the centers when patients are being treated. As I'm sure you're fully aware, there was none of that, that we could do during the course of the pandemic. And in fact, we're about 2 steps removed from all of those activities. Now this puts us in a sort of -- put us in a somewhat uncomfortable position, and we're basically running almost a real-world study during that period in this very fragile population. Despite that, we were able to actually replicate the adverse event profile, which obviously was very attractive coming from our HER3 Phase I studies that we have conducted before. We're able to see, and this is now in a larger data set, here, we're looking at 92 evaluable patients for safety. We were seeing that we had less than 4% of patients with high-grade cytokine release syndrome, less than 8% with high-grade ICANS or neurotoxicity. This is a remarkable outcome and is comparable and potentially a tad better than what we have seen with Blincyto during the registration studies. So what we're able to do really with that is we have clearly replicated the highly attractive profile of the product. From a safety perspective, we've been able to demonstrate a very high level of clinical activity. And we also have been able to actually, when we're looking at the persistence, which was on the hallmark of the program, we've been able to show that indeed the initial persistence we're seeing in these patients actually is tracking on the persistence that we've seen in the ALLCAR study. And we're also included there the Phase Ib data, which gives us obviously a longer follow-up of a year more in these patients as well. That gives a very consistent outcome in this study, which obviously makes us very optimistic about the further success of the study and the program. Now triggered by these outcomes was a $35 million milestone from Blackstone, which was linked to the program reaching the primary endpoint and based on the very strong statistical outcome that we've been able to achieve here, we also achieved, actually, the overall ORR set for the full study at this interim data point already. And so that, together with the transformation of the excellent safety profile, triggered at least $35 million milestone quite ahead of the time when it was originally designed or expected to be triggered. And so -- and finally, obviously, when we think about where we are operational with the study, obviously, the patients are all enrolled in the morphological cohort. And obviously, we're aiming now for -- and looking forward to the data release that is planned for ASCO middle of next year. Moving to Slide #10. As we're moving and sort of into the ASH data set now, the opportunity we had at this ASH and presented last night, is to provide a long-term follow-up from the ALLCAR19 study. So this is really the study that's sort of leading Is on the leading edge of the data in the ALL population because now we have actually observation of patients that are in remission for up to 48 months. So this is a remarkable robust and mature data set at this point in time. And as you can see on this slide, as you go from the bottom up, you see patients obviously that did not respond, patients that relapsed quickly, either with CD19 loss or due to loss of persistence. CD19 loss is in the yellow circles. And in fact, patients that did actually relapse with loss of persistence have CD19-positive disease and are shown with the red circles. But as you see, as you go further up, you see a population of patients. In fact, there are 8 patients out of the 20 that actually are in between 24 months and 48 months of follow-up. And out of those 8, 7 haven't received any additional therapy. All those 7 patients actually have ongoing persistence in there of CAR T cells up to 48 months now observed. One of the patients did receive a stem cell transplant early on. This was actually our first patient who was treated, and there was no clarity whether we could induce longer-term remissions. So the patient got transplanted. Obviously, as a consequence of the transplant, the CAR T cells were wiped out but also that patient now is reaching almost 4 years of follow-up. So in short, we're looking at 35% of the patients that have received no other anti-leukemia therapy that are between 2 years and 4 years of follow-up. And that gives us a lot of confidence about the ability of the product to actually into this long-term remissions in a patient population where we had a really hard time inducing that, frankly, with any therapeutic modality available to date. Now as we're sort of going on to the next slide, on Slide 11, what you see on the left-hand side is, in fact, a spider plot with the actual persistence data for all of the patients. And in fact, when you look at that, you do see that at 24 months, you got 7 patients that all have measurable persistence. Those are the 7 that are actually in ongoing remission. So a very unusual outcome and obviously, very unusual to be able to actually measure persistence that far out. Now from there, obviously, we also actually continue to explore the activity of obe-cel in non-Hodgkin's lymphoma, and we're moving to Slide #13. As we're sort of actually progressing, the follow-up with these patients and adding a few more patients, I think there are a number of interesting observations. First of all, we start to see a very high level of activity, not only in the non-Hodgkin's indications where we have, with the exception of one patient, all achieved a metabolic CR. But we also see actually sustained responses in CLL. And that also is -- in all cases where we see those responses, we also have an MRD-negative bone marrow in every one of these patients. So we start to see meaningful duration of responses there, and we continue to follow these patients. DLBCL gives us, I think, a very nice data set that continues to mature nicely. In DLBCL, we had 7 of 8 patients achieved a metabolic CR. One of the patients, unfortunately, died of COVID after about 8 months being in metabolic CR. But everyone else actually continues in remission going forward, and we have now most of these patients post 6 months of follow-up, and that starts to give us quite a bit of confidence. And indeed, we should be able to actually see a very meaningful clinical activity in DLBCL. Mantle cell, we continue to observe the patients, obviously, a very nice duration that we're starting to pick up. We had one patient at 6 months with a skin lesion that we have reported on prior and actually is also -- after dealing with the skin lesion, he's actually progressing in remission still. But obviously, not within the study. Now in follicular lymphoma, we had an interesting picture that is emerging, which is up to 12 months; first of all, everybody achieves the metabolic CR. And we then have lost one patient before 6 months due to COVID, which is the black square, and then as we go to 12 months, we still got everybody or almost -- actually, we got everybody in remission. And then we see between 12 months and 24 months, some of the patients are actually starting to relapse. So clearly and quite consistently what we've seen with follicular lymphoma across, I think, every modality is that it does not look to be a curable disease. And so what we're looking to do is buy time. Overall, the outcome looks actually very attractive. What's interesting about the 4 patients is that all 4 patients had prior bendamustine therapy. And that may actually be an element there that we need to investigate further. It's also a feature that has come up in the context of the MCL work with Tecartus, where also bendamustine appears to have an impact on the quality of the T cell and persistence -- expansion persistence as well. And that's an area we're looking into more detail to see whether there's a significant relationship there between bendamustine and outcomes here, but it's certainly interesting observation at this point. Overall, we're very enthusiastic actually about the program. We clearly have a very high level of activity and aggressive forms of non-Hodgkin's, and we need to obviously understand more about follicular patients, all of which, by the way, have actually relapsed with CD19 positive disease. Now moving on to the update on pediatric ALL. As you remember, the program here builds on the obe-cel backbone. And it's a highly potent CD22 CAR. We already reported on that middle of the year at the EHA and we have shown that indeed we could get -- we're obviously aiming to sort of get at patients that have either lost CD19 expression prior or patients that had extramedullary disease, which, as I pointed out before, is an indicator for very poor outcome. Now as you can see in the updated data on Slide 16, and it was more detail on the poster later today, you do see that, indeed, the product is highly active, has a very good safety profile. And despite the fact that we had 3 patients here with CD19-negative disease and 4 patients with extramedullary disease, it gives us a very strong outcome, both from a CRA perspective but also as we're seeing the patients sort of progress over time. As you know, we're also, with this program, currently testing a shortened manufacturing process as well, which is sort of the next step that we're running together with our collaborators at UCL. So overall, I think we have demonstrated a very nice outcome for confirmation of the adult ALL data in our FELIX study, very nicely tracking what we have seen before in the ALLCAR study, both on efficacy, on persistence as well as on safety and we're obviously now getting ready for getting that product to the point where we have a full data release plan for ASCO next year. ALLCAR19 study is really kind of the leader in terms of generating data and at all, ALL and gives us, I think, a good view of what the product is actually capable of doing. The fact that we're seeing 35% of the patients in sustained long-term remissions is fantastic and gives us a lot of confidence that we have a product here that at least has the potential to be transformational for some of the patients in this very difficult-to-treat disease. And also important, obviously, the connection between long-term outcome and CAR T persistence which is obviously clearly a critical feature and a unique feature that we're seeing with obe-cel. When we look into the non-Hodgkin settings and CLL settings, I think, I would say, a fantastic level of activity, very good safety profile and we start to build, I think, a good view of what are the indications that we're going to focus on as we're moving forward, obviously, with an expectation that we want to actually start a non-Hodgkin's study towards the end of next year. And then finally, AUTO1/22, obviously, really the first step in the life cycle for obe-cel, telling us that we have a product and indeed, that's highly active in a setting where would have actually expected a substantially reduced CR rate. And in fact, we're coming out at 83%, which has been really remarkable. So with that, just a final update on AUTO4, 5. You remember the opportunity here in T cell lymphoma is significant, quite comparable actually to what we're seeing in adult ALL. Very challenging disease setting and really the difficulty is coming up with good targets to go after. We have a unique set of targets that we're going after. In our case, the isoforms of the PCR receptor beta chain and that gives us an opportunity for targeting the disease without actually, at the same time, having a negative impact on the entire T cell compartment. As you remember, we've provided an update on this study at EHA. We have now actually longer follow-up when we have now first patients that are in complete remission at the high dose level at 9 and 12 months, which I think starts to give us a really good understanding of clinical benefit that we're starting to induce and we can actually start to articulate. Now this program is very important. We obviously start with a product that, actually, when you collect the T cells, you have to obviously be careful because part of the T cells could actually contain T cell lymphoma cells. And so the first step we're doing is actually getting rid of all the cells that could -- all cells perhaps that could actually contain lymphoma cells and then actually go into the actual manufacturing process. So that process in that regard is different from what we normally would do. And as you can imagine, there's a lot of the learnings from obe-cel that we can actually have flow into this program. And that's actually what we've done. And when you look in Slide 22, you can see where we're headed. So the old process took us about 10 days to get the product done. Had sort of a mixed phenotype with quite an extensive proportion of sales, more than half of the cells were effector memory or TEMRA. So these are kind of the cells that are ready to shoot, but they have a much harder time to proliferate and actually sustain their presence over time. In order to actually have a product and has a sustained presence over time, you need to actually make sure it's sort of heavily up-sided on the T cell memory at the naive T cell side. And so the process that we actually modified is now shown on the right-hand side of the shorter process. And as you can see, compared to where we were before, we have virtually no effector memory nor -- and TEMRA cells was above 50% before, now we're at about 6%. So it's a massive difference in terms of the product property and the quality of the product. And this actually is now going back into the clinic, and we're treating another 6 patients now with this change manufacturing process, and we're obviously very excited to sort of see kind of where that gets us to, but the sense is that we have a product that is much healthier and has an opportunity to actually expand, proliferate as well as persist, obviously, much better given the composition that we're seeing here. So this is kind of the direction that we're taking with the T cell lymphoma program, obviously, a very exciting one and a very significant difference in terms of where we are. So in terms of concluding remarks and moving to Slide 24. I think I'd like to start out, obviously, with the transaction we've done November last year with Blackstone Life Sciences, which was sort of 2 components with $100 million equity investment and $150 million in product financing, $50 million of which were paid in at the signing last year and there was $100 million of payments on the product financing side that were triggered by milestones and progress and success within the program. And so what we just talked about at the entry of this presentation is we have hit 2 important milestones, each actually coming in at $35 million, a total of $70 million. And they were linked to basically reaching the primary endpoint and confirm with the safety in the FELIX study, that's number one. The second one was actually for the key activities that actually characterized the performance and qualification of the manufacturing process for obe-cel, which is a key risk-reduction step also key sets of data that form the basis for a BLA filing as well. That triggered the second $35 million milestone. I think it's important to also state that both of those triggers ahead of the planned timing because of the excellent execution we have this year, but also the success we had, both on the clinical and at the manufacturing side. Now the cash balance at the end of the quarter -- of the third quarter was $163 million. That did not include $19.1 million in tax, R&D tax credits that we received from the U.K. government beginning of the fourth quarter. Also, we're adding $70 million from non-dilutive funding from the 2 milestones from Blackstone. And obviously, the proceeds from the public offering, which is expected at $150 million. What this does is it actually extends our cash runway into 2025. And then we're looking at the news flow on Slide 25, obviously, a heavy focus on obe-cel as we go through the course of next year. There's a further more detailed analysis we're going to show on the longer-term follow-up and long-term survivors, frankly, in the ALLCAR19 study expected for the early part of '23. We then obviously provide updates on the non-Hodgkin's trials, but most importantly, we're planning for the FELIX Phase II outcome middle of the year. So that's going to be also the key next fundamental news flow for obe-cel. And then as we're looking to the end of the year, we also do expect obviously update in terms of long-term follow-up from the FELIX study, which I think will round out the overall data very nicely with the targeted BLA filing as well towards the end of next year. The final indication that also has been active in, and we also expect to update you probably middle of the year is the CAROUSEL study in patients with primary CNS lymphoma, which obviously has progressed very nicely, and we'll sort of update you also middle of the year. The pipeline we just went through, I think, plenty of opportunity on the ongoing clinical programs for additional updates. But we're also, on the academic side, are collaborating with UCL on AUTO8 in the multiple myeloma and also AUTO6NG in neuroblastoma, which we'll sort of provide updates towards the end of next year and into 2024. And then very important on the manufacturing side, all the data that we're generating on the commercial manufacturing side, obviously, will be part of the BLA filing and sort of licensing process. There is an enormous amount of work that obviously will be done during the first half of next year and into the early part of the second half of next year, and we'd also expect them to trigger the GMP license from the MHRA in the second half of the year -- next -- second half of 2023 as well. And then obviously, leading into the BLA filing towards the end of the year. So that's kind of the key news flow and sort of the key activities, obviously heavily focused on obe-cel and delivering the program through the registration -- into and through the registration process and obviously well set up at this point from a financial perspective to be able to execute on this program and deliver what we believe is an important therapeutic option for patients with ALL. All right. At this point, I'd like to stop here, and I'm happy to take questions.

[Operator Instructions] And our first question comes from James Shin from Wells Fargo.

Hello, can you hear me?

We can hear you, yes.

I got a couple. Starting with the B-ALL, you mentioned obe-cel's expansion and persistence and FELIX is tracking ALLCAR. I know it's still early, follow-up only 6.4 months for FELIX, but what are your thoughts on FELIX eventually or potentially matching the 3-year response we've seen in ALLCAR19. And then secondly, for AUTO4, have you looked to see if there's some sort of co-stimulation components that may be helping responses given AUTO4 does not seem to be expanding in the periphery?

So the first question is the statement, I think, related to statement that I made that the product is tracking nicely also on persistence. Now we -- the median follow-up of the 50 patients about 6 months, but also when you then actually include obviously the patients in the Phase Ib cohort, whether we have about the median of the year, mostly more than a year at this point. So it's actually quite a substantial amount of data that we do have in terms of persistent observation in patients over an extended period of time, not just for the 3 months, which is the minimal duration that we have in the interim analysis. And what we do see is that the curve tracks very nicely. And obviously, when you look at competitive programs, there is zero -- there is actually zero persistence at 6 months by PCR and by flow, you lose the signal in 3 months. So even if your observation is for 6 or 9 months for a good jump with our patients, actually, it will tell you always at that point in time that the persistence profile is very different. And in fact, when we look at the curves that we've had on median persistence from ALLCAR, we're tracking very nicely along that. So that is kind of where we are with regards to the persistence. In terms of predicting long-term outcomes, long-term outcome is clearly, as we can see from the ALLCAR study linked to persistence, it's a prerequisite. And I think what we're seeing is, overall, that we're starting to build, I think, the high level of confidence around also from the Phase Ib component of the FELIX study that indeed, we do see a substantial proportion of the patients getting into long-term remissions. But obviously, that requires full follow-up and update. And I think we're starting to see, I think, a good feel once we have all patients past 1 year of follow-up. But it will take some time to actually get enough maturity into the data set to sort of make that firm statement.

And then what about the AUTO4? Is there, maybe, a co-stimulation component to help the responses?

That's an interesting question. It's obviously one that's very hard to test. What we do know is that the product obviously is in the lymphatic tissues in the tumor stations and we could visualize that by doing IHC analysis, et cetera. And so we can see the presence of the CAR T cells. We see that they're expanded in that tissue. And with that, we know that it's clearly is active at that space. Where there's a co-stimulatory component, I think that's incredibly difficult to decipher. You could probably do a bit of work on nonclinical models, but frankly, the killing activity of the CAR T cells will always exceed anything you could sort of see as a potentially co-stimulatory components. So I'm not sure you can easily piece it out.

If I may, just one more follow-up on CARPALL for 1 to 2, what is the threshold for MRD negative? Is it 10 to the minus 5 or minus 6? And then I'm just trying to understand the durability for MRD negativity. It looks like 5 out of 10 responders remained an MRD-negative CR out to about 9 months. But is this including the patients that received subsequent therapy? And what is a good benchmark? I've been looking through Kymriah's durability data, and I can't really find a good durability number for MRD negativity.

I think -- James, I think, first of all -- so the technical question first. The technical question is how is it done? So this is -- the assessment typically is done by -- in those patients in the academic side is done by PCR or by flow. And the sensitivity that you have with PCR flow is 10 to the minus 4. You could push it a bit more, but it's sort of in that ballpark. In terms of the methodologies that are being used here. So this is not based on NGS, not the way we're doing it in the pivotal study. Because NGS is typically not available or is not available at all centers, some centers have access to it, but some don't. So that's the first, that's the technical question. The second question is an interesting one because you're asking for, well, what should you look for in terms of comparison? The short answer James is there is no comparison. These patients do not receive CAR-T therapy today because they're post-Kymriah or they have extramedullary disease, which excludes them from receiving Kymriah. So this is a Kymriah ineligible population. And in short, there is no data available for these patients, except that you know they're doing extremely poorly. And so for us to actually see them coming out as an 80% or 83% molecular CR rate is absolutely phenomenal. Remember, some of them were CD19 negative and the rest actually end with extramedullary disease. So this is an incredibly difficult population. And when you look at extramedullary disease patients versus normal ALL patients, you do see a decrease of about 50% in ORR usually in those patients. That's what you have to actually -- that's both the order of magnitude for that we're looking at. So if you see them come out at 80% is actually astonishing. But the short answer is there is no comparison in terms of data sets that we can look at. And that makes -- and that's sort of the fact that we see something that looks like Kymriah in a much better population is in of itself quite remarkable.

And our next question comes from Matthew Phipps with William Blair.

Congrats on the positive interim. First off, for the FELIX interim, I assume all of these 50 patients were treated with fresh leukapheresis products. I remember as -- a year ago, I think you guys switched to the fresh product.

Matt, thanks for joining, and I really appreciate your joining the call. Yes, all patients, the manufacturing process is a fresh in frozen out process. And the reason fresh in this indication is that you have many patients with very high leukemic burden. So you collect the cells you collect can contain a very large amount of leukemic cells, and that actually is a starting material, which is not that easy to manage and certainly not one that you want to freeze and thaw, so fresh in this is actually why we went to a fresh in process for all patients.

Okay. And then the press release does say CRS with grade 3 or higher. So does that mean we should assume there was grade 4? Or you're just putting grade 3 higher as a kind of standardized practice?

I think it has had a lot to do with that fact, it's a standardized practice. The differences are -- there's big differences even within the grade 3s and grade 4s. Overall, I think what we can say is that all patients actually recovered very rapidly. And responded well just to the standard intervention that you have for CRS as well as for ICANS for that matter.

Okay. Then so for AUTO1/22, I was curious if you had data yet on the persistence of those cells. And just kind of when you're seeing these relapses around 9 months that are dual antigen positive, are they -- are you losing persistence of the CAR Ts or is there something else driving that?

So what we're seeing -- in part, we do see lots of persistence, which is what you would expect. Patients that actually had prior other CAR T therapy are known to actually show poor persistence. And if you look at retreatment with Kymriah over time, there's a series of examples there. So that's, I think, one of the things you do expect. The second is, of course, with patients that have CD19 negative disease. So that's basically overly carried than on the CD22 side and already have been exposed before to CAR T, so those clearly have a significant impact. And then finally, on the extramedullary disease, that also is now tissue that is more difficult to get to. The less CAR T cells that actually will get to tissue because they're still homing into the marrow. And I think that is sort of where you also would expect to see some impact. But we do see an impact both on loss of persistence. What we do not see is we do not see target loss as a reason for relapse. And I think that's obviously the key thing where we're looking for is do we actually -- are we closing the door for target antigen loss? And the answer is clearly, yes, we do.

Okay. And then last question. The updated runway guidance with the new capital. I guess, does that include or assume additional trials in NHL with obe-cel, so some expansions in maybe some of the specific cohorts?

So it does include, obviously, the completion of the current pivotal study, including the MRD cohort. It includes a smaller pediatric trial that is an obligation that we have to sort of do from both an FDA perspective, but also the requirements for EMAs as well as MHRA. There is, obviously, all the activity related to the manufacturing as well as commercial preparation. And it also includes the start-up of a non-Hodgkin's trial towards the end of 2023.

And our next question comes from Mara Goldstein from Mizuho Group.

I just wanted to ask for a bit of clarification on the obe-cel data in the ALLCAR study. And the CLL treated patients where you have those unconfirmed MRD, when would you anticipate that those would begin to confirm? And then just a follow-up question after that.

So what we have is that we have molecular complete remissions that we see in the bone marrow. And what we do see from an overall response assessment is we do -- it's categorized as a partial response because there's slightly large lymph nodes, 1 or 2 in each one of the patients that we're picking up, the characteristics there is that it's just basically the diameter of the lymph node that you look at, and you're not looking at the metabolic readout because the cells do not have an awful lot of metabolic activity. And so this is purely by size. But what we see is that these PRs clearly are sustained over time. And so at this point, I think difficult to tell whether these are PRs, or should actually be reclassified. But at this point, we're carrying them as PRs, but with -- from a bone marrow perspective, molecular complete remissions from a bone narrow perspective. So these are not unconfirmed MRD status. This is confirmed MRD status, but they're PRs.

Okay. All right. I appreciate that. And then just on the manufacturing process for AUTO4, can you just discuss what the success rate of the sort of new processes versus the old process? And whether you're seeing higher activity at lower doses given that you have higher memory T cells in there?

So first off, in terms of our ability to manufacture for patients, we've actually been able to manufacture for all patients in this trial. So we -- there is nothing we can really report on differences here. We're successful with all the patients that we manufacture for. Obviously, the new process, the numbers are still too low because we just started actually that cohort. And to the specific question related to potential outcome, that's actually too early because we're literally just -- we've gone through dosing of the first patients, but there is more information that we need there.

Okay. And then just as it relates to Blackstone, you've received those 2 milestones relative to the current agreement. Can you just speak to what the next opportunity is from that program?

Right. So there is a total of $150 million project financing in the transaction. Of that, we have now actually received $120 million, $50 million upfront, now 2x $35 million in milestones, that's $120 million. So the least $30 million as the last milestone, which is a regulatory milestone.

And our next question comes from Gil Blum from Needham & Company.

Congrats on the progress. So maybe a first one on the CRS and ICANS observed on FELIX study. So how do you feel these compared with current ALL therapeutics? And how do you think these are going to be managed in the community?

Right. Really good question. So first off, when you look at how they compare, so if you look at Blincyto, which is the bispecific T-cell engager, which is the standard of care in the setting. We do actually compare really well. Blincyto has about 5% to 6% high-grade CRS. We have less than 4% and has about 13% high-grade ICANS, but about 60% of the patients with some form of ICAN. So we're -- if you compare to that, we're at less than 8% on high-grade ICANS and about less than 30% of ICANS of any grade. And so that gives us, I think, even to Blincyto, at least as good as, if not better adverse event profile. What we do see, if you compare to the CAR T side, obviously, most of the programs on the CAR T side, the experimental ones as well as the CAR T is an approved product, have shown very significant levels of toxicity in the range of 26% high-grade cytokine release syndrome versus less than for 35% high-grade ICANS with close to 90% ICANS of any grade versus less than 8% of high-grade ICANS and by 1/3 of the patients experiencing or less than 1/3 experience some form of ICANS with obe-cel. So there's big differences there. Now when you look more carefully, and this is obviously our side, it's a 92 patient data set. This is not a small data set we're talking about. So when we then look into actually what's driving adverse events, there's clear relationship to tumor burden. And what we do see is the patients below tumor burden actually do even better. And I think that is actually what I think will ultimately become an important guide is that there will be likely a guide towards -- that's related to tumor burden in some way that actually will give us sort of an indication for patients that are suitable for sort of hospital outpatient use of the program downstream. But I think that is sort of one of the key things that we're starting to work through as we're going through the full collection of the data of the ALL study and then a sort of a number of analysis that are ongoing in that regard. But I think there's going to be, I think, a good way to determine and understanding what proportion, what type of patients are suitable for outpatient use. Important as a point of reference, obviously, also team to burden related. There is a good number of patients with Blincyto that are actually managed in the hospitalized patient setting as well. And obviously, as with the safety profile we have, obviously, have a very attractive opportunity here.

That was very helpful. So another question on the long-term data from obe-cel, it was pretty interesting to see that CD19 negative relapses appear to happen earlier than the CD positive ones for the most part. Let's just -- I find that as a surprising insight given long-term clonal pressure should lead to CD negatives resistance, right?

I mean, it's a really interesting question. In the end, when you think about CD19 negative relapses, it's basically a selection process where you sort of select out the CD19 negative clone. And clearly, that clone either has to preexist or has to be sort of generated early on when there were still a lot of CD19 positive cells in the body. The longer you go, the less CD19 positive cells you have because the therapy has taken them out and actually taking them out very, very quickly. And in that regard, I think it's in terms of tumor mass removal happens within 2 weeks pretty much. So the majority of CD19 positive cells are gone in 2 weeks. And so they either have -- until that CD19 negative clone has to exist almost in that pool because the remaining cells that are sort of left standing that you sort of then put pressure on a longer period of time. That's just so few in comparison that it is just not that likely that you will get to a mutational event that actually would give you that late CD19 negative relapse. I think that's the way probably I would look at it just the question of statistics and probability, frankly of when that event actually has to occur, you still actually be sorted out with the therapy as other your sorting device to sort of look for the CD19 negative relapse.

All right. And the last question on T cell lymphoma. It's probably worth putting in context how difficult is to get patients into long-term remissions with standard of care. I don't think when it comes to PT cells usually refractory pretty quickly.

I think that's a really good point, Gil. And it was interesting when we did the -- our analyst call at the EHA, one the experts from Memorial Sloan Kettering actually talked to us. And his statement basically, well, you don't get CRs at that stage of the disease. So the fact we got CRs was already in his view, remarkable. They actually did actually see CRs actually survive and sort of the extend over 9 to 12 months, I think, gives us a lot of confidence in terms of the actual clinical activity that we're observing. So I think it is an excellent point, and it's certainly one of the real challenges that we have in at that stage of the disease, that any current elements of the standard of care does not actually give us complete remissions anymore. So they actually see complete remissions that they actually can be sustaining days is the way that we just call in this setting.

Maybe another relevant factor there the infection rates were actually not that high. It's another...

That's right. That's correct. That's something we did look at in the context of the -- also talk more about that in the context of the EHA presentation middle of the year that we didn't pick up actually increased rates of infection, which I think is obviously one of the design characteristics here is to be able to skip the tumor without actually rendering the cells more immunosuppressed -- the patients more immune suppressed. And now that, I think, looks very much and that increase is holding up and holding up over time.

And our next question comes from Dev Prasad from Jefferies.

This is Dev on for Kelly Shi at Jefferies. Just a couple of quick ones. When can we expect to see that morphological cohort data? Will it be alongside the full FELIX data mid-next year? And second is now you are -- like what is the next program company it will be focusing following obe-cel? That's it for me.

Thanks a lot, Dev. Thanks for joining. The first question is related to the morphological cohort. So that obviously is still the primary cohort we're looking at. And the planned update, I would say, for full data is ASCO. On the MRD cohort, which is the separate cohorts that we're running, we're currently expecting that we have a first data update at ASH next year. So that's the timing around there. And then with regards to the next program, obviously, first of all, we got to get this program over the finishing line. So that's going to be where the primary focus will be for the business. As I indicated, we expect to add non-Hodgkin's indication towards the end of next year. And then obviously have significant opportunity between both AUTO1/22 as well as AUTO4. And obviously, we'll see how these programs progress and then actually, we'll make the decisions accordingly. But are certainly interesting opportunities also with the pipeline that we're currently working on together with our academic collaborators. So I think overall, I think very, very interesting, obviously, stretch ahead of us, but very much focused on execution of obe-cel and getting this product to market.

And our next question comes from Eric Joseph from JPMorgan.

This is Noah on for Eric. A quick question from us. Is there any color that you can give on the preponderance of extramedullary disease and the balance of the FELIX study in patients that haven't been reported on for efficacy yet? Are these patients entering the study with extramedullary disease? Or what is the expected duration of response in these patients?

Yes. Really good question. Thanks a lot. So extramedullary disease patients actually are pre-existing conditions typically. So -- and it's very well described to patients when you look at patient relapse is after Blincyto, you have an elevated level of patients that have extramedullary disease, and that's true for other intensive therapies that we see in adult ALL. And it's -- basically, it's sort of an evolution of the disease going from a pure bone marrow disease to one that actually spreads further in the body and then that point actually becomes much harder to treat. As I've indicated, quite often you see when you look at standard of care with Blincyto, other therapies that your objective response to overall remission rate actually goes down probably by about 50%, give or take, depending on the program you're looking at so it's a very significant impact on the ability to respond and the responsiveness of the disease once it reaches that stage. In terms of durability at this point, there is sort of limited information, I think. And I think that's something we're going to see. The level of these -- for these types of patients was less than some of the prior pre-pandemic trials. I think what we're seeing is in our trial is a consequence, in part of the pandemic and that patients that were kept on standard of care for as long as possible and try to avoid having to move them into hospitals or frankly have them travel across the country to join a clinical trial due to their immunosuppressed status that they do have. And I think we're seeing a consequence of that and was that a higher percentage of patients in that and with that, a sort of slightly more advanced state of the disease. We haven't given the details on the percentages, but it's meaningful enough that we believe it is important to state. And we'll sort of provide also a detailed update as well as the behavior of those patients at the planned presentation at ASCO.

Thank you. And I am showing no further questions. This concludes today's conference call. Thank you for participating. You may now disconnect.