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. Good morning, and thanks for joining us and taking part in today's call, which will be covering the data we're presenting at the ASH conference. This is Olivia. On the call, as usual, are Dr. Christian Itin, our Chief Executive Officer, and Dr. Lucinda Crabtree, our Chief Financial Officer. 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 two. Please make sure you're familiar with the disclaimer slide. With that, I'll hand over to Christian to summarize the data, and afterwards we will welcome your questions. Over to you, Christian.
Well, thanks a lot, Olivia. Welcome everybody for joining this morning. Really appreciate you taking the time. Obviously, you know, 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 look into the clinical data updates that we're running at ASH. My key presentation yesterday looking at long-term follow-up on our ALL patients, as well as longer term follow-up on the non-Hodgkin lymphoma and CLL cohort that we continue to work on.
Additional follow-ups with the IR two 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 two 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 two milestones under the Blackstone agreement due to the progress both in the clinical as well as the manufacturing side of the business related to obe-cel.
We obviously did announce also at the end of last week, a $150 million offering, which we expect to close early this week. The expected cash runway with those additional events happening, is extended into 2025. Moving to slide number five. As you all remember, obe-cel obviously is a product with a very nicely differentiated mechanism of action. We generated a product here that engages the T cells, engages the target cells in a as physiological way as possible, gives us a high level of activity, but avoids the overactivation of the CAR T cells.
All of that is really driven by the binder that we're using, which gives us a fast on rate, but also 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've now been able to see across a range of indications. Focusing on ALL, just on slide six, 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 are in need of therapeutic intervention, and in that sense, the market actually hasn't changed in terms of its size. We're also obviously, in the course of last year and into this year, have 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. When we go onto slide number seven, 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 so-called morphological disease. These are patients with more than 5% tumor burden.
The primary endpoint is based on the achievement of complete remissions that can come in two flavors in ALL, either complete remissions with full recovery of neutrophils and platelets. These are conventional CRs or complete remissions where there's an incomplete recovery of neutrophils and platelets, which are CRIs. 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, eventually 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 is including patients that have lower disease burden, so-called minimal residual disease, which is characterized by disease that's less than 5% disease burden in the marrow. 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 the stage at which of the relapse at which physicians want to intervene and do intervene in terms of the therapeutic activities.
All of this obviously is designed to 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. On slide eight, we're looking at the sort of top-line outcome of the FELIX study. The first data that we have reported on the efficacy side is based on a pre-specified interim analysis, based on 50 patients. The data are based and reviewed by an independent data monitoring committee, is looking first at the overall response rate, the primary endpoint, in this group. We have demonstrated that the product achieved 70% overall response rate in these 50 patients.
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 phase Ib, 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. Extramedullary disease is, in essence, the leukemia that has managed to actually, the gain of function, managed to escape from the bone marrow and settle 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.
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. 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 immune-compromised patients that are very fragile and with a lot of comorbidities in any normal situation, you'd be very close to the trial sites. You would be very close to the patients. You'd 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. In fact, we're about two steps removed from all of those activities. This puts us in a sort of, put us in a somewhat uncomfortable position that 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 three phase I studies that we had 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're 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. 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 ALL CAR study.
We're also included there the phase Ib data, which gives us obviously a longer follow-up of a year or more in these patients as well. It gives a very consistent outcome in this study, which obviously makes us very optimistic about the further success of the study and the program. Triggered by these outcomes was a $35 million milestone from Blackstone, which was linked to the program reaching the primary endpoint. 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.
That, together with the confirmation of the excellent safety profile, triggered this GBP 35 million milestone quite ahead of the time when it was originally designed or expected to be triggered. Finally, obviously, when we think about where we are operational with the study, obviously the patients are all enrolled in the morphological cohort. Obviously, we're aiming now for the... and looking forward to the data release that is planned for ASCO middle of next year. Moving to slide number 10. As we're moving and sort of into the ASH dataset now, the opportunity we had at this ASH and presented last night is to provide a long-term follow-up from the ALLCAR19 study.
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. This is a remarkable, robust, and mature data set at this point in time. 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 they're shown with the red circles. 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. Out of those 8, 7 haven't received any additional therapy. All those 7 patients actually have ongoing persistence in their 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 that was treated, and there was no clarity whether we could induce longer-term remissions. The patient got transplanted. Obviously, as a consequence of the transplant, the CAR T-cells were wiped out. Also that patient now is reaching almost 4 years of follow-up.
In short, we're looking at 35% of the patients that have received no other anti-leukemia therapy that are between two years and four years of follow-up. That gives us a lot of confidence about the ability of the product to actually induce long-term remissions in a patient population where we had a really hard time inducing that, frankly, with any therapeutic modality available to date. As we're sort of going on to the next slide, in 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. In fact, when you look at that, you do see that at 24 months you've got seven patients that all have measurable persistence. Those are the seven that are actually in ongoing remission.
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 lymphoma, and we're moving to slide number 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 indications where we had, with the exception of one patient, all achieve 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 a MRD negative bone marrow in every one of these patients.
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 and continues to mature nicely. In DLBCL, we had 7 of 8 patients achieve a metabolic CR. One of the patients unfortunately died of COVID after about 8 months in being in metabolic CR. 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 six months with a skin lesion that we have reported on prior. Actually is also after dealing with the skin lesion, is actually progressing in remission still, but obviously not within the study. 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. We then had lost one patient before six months due to COVID, which is the black square. As we go to 12 months, we still got everybody, actually we got everybody in remission. We see between 12 months and 24 months, some of the patients actually starting to relapse.
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. 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. 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. That's an area we're looking into more detail to see whether there's a significant relationship there between bendamustine and outcomes here.
It certainly, 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 in aggressive forms of non-Hodgkin's, and we need to obviously understand more about the follicular patients, all of which, by the way, have actually relapsed with CD19 positive disease. Moving on to the update on pediatric ALL. As you remember, the program here builds on all the obe-cel backbone and adds a highly potent CD22 CAR. We already reported on that middle of the year at EHA.
We had 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. As you can see in the updated data on slide 16, and there's more detail on the post later today, you do see that indeed the product obviously is highly active, has a very good safety profile.
Despite the fact that we had, you know, 3 patients here with CD19 negative disease and 4 patients with extramedullary disease, it sort of gives us a very strong outcome, both from a CR perspective, but also as we're seeing the patients sort of progress over time. As you know, we're also with this program, we're 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. Overall, I think we have demonstrated a very nice outcome for and confirmation of the adult ALL data in our FELIX study, very nicely tracking what we have seen before in the old CAR study, both on efficacy, on persistence, as well as on safety.
We're obviously now getting ready for getting that product to the point where we have a full data release planned for ASCO next year. ALLCAR19 study is really kinda the leader in terms of generating data in adult 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.
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, obviously a fantastic level of activity, a 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 study towards the end of next year.
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 we would have actually expected a substantially reduced CR rate. In fact, we're coming out at 83%, which has been really remarkable. With that, just a final update on AUTO4/5. You remember the opportunity here in T-cell lymphoma is significant. It's 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 TCR receptor beta chain, 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've now actually longer follow-up, and we have now first patients that are in complete remission at the highest 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 with this program, it's 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.
The first step we're doing is actually getting rid of all the cells that could cell types that could actually contain lymphoma cells, and then actually go into the actual manufacturing process. That process with that regard is different from what we normally would do. As you can imagine, there's a lot of the learnings from obe-cel that we can actually have flow into this program. That's actually what we've done. When you look in slide 22, you can see where we're headed. The old process took us about 10 days to get the product done. Had a sort of a mixed phenotype, with quite a an extensive proportion of cells, more than half of the cells were effector memories or TEMRA.
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 that has a sustained presence over time, you need to actually make sure it's sort of heavily sided on the T-cell memory at the naive T-cell side. The process that we actually modified is now shown on the right-hand side. It's a shorter process. As you can see, compared to where we were before, we have virtually no effector memory nor... and TEMRA cells. It was above 50% before. Now we're at about 6%. It's a massive difference in terms of the product property and the quality of the product.
This actually is now going back into the clinic, and we're treating another six patients now with this changed mode manufacturing process. We're obviously very excited to sort of see kinda where that gets us to. 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. This is kind of the direction that we're taking with the T-cell lymphoma program. Obviously a very exciting one with and a very significant difference in terms of where we are.
In terms of concluding remarks and moving to slide 24, I think I'd like to start out obviously with the, you know, the transaction we've done November last year with Blackstone Life Sciences, which was sort of two components. Was a $100 million equity investment and a $150 million in product financing, $50 million of which were paid in at the signing last year. There was a $100 million of payments on the product financing side that were triggered by milestones and progress and success within the program. What we just talked about at the entry of this presentation is we have hit two important milestones, each actually coming in at $35 million, a total of $70 million.
They were linked to basically reaching the primary endpoint and confirming 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 triggered ahead of plan timing because of the excellent execution we had this year, but also the success we had both on the clinical and the manufacturing side. Now, the cash balance at the end of the quarter of the third quarter was $163 million.
That did not include GBP 19.1 million in R&D tax credits that we received from the UK government beginning of the fourth quarter. We're adding GBP 70 million from non-dilutive funding from the two 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. We're looking at the news flow on slide 25. Obviously, heavy focus on obe-cel as we go through the course of next year. There's a further more detailed analysis we're gonna show on the longer term follow-up and long-term survivors frankly, in the ALLCAR19 study expected for the early part of 2023.
We then obviously provide updates on the non-Hodgkin's trials. Most importantly, we're planning for the FELIX phase II outcome middle of the year. That's gonna be obviously the key next fundamental news flow for obe-cel. 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 a targeted BLA filing as well towards the end of next year. The final indication that obviously we've 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. We're also on the academic side are collaborating with UCL and AUTO8 in their multiple myeloma and also AUTO6NG neuroblastoma, which will sort of provide updates towards the end of next year and into 2024. 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 licensing process. There's 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.
Would also expect then 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. 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. 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.
Thank you. As a reminder, to ask a question, you'll need to press Star one one on your telephone. Please stand by while we compile the Q&A roster. Once again, that is Star one one to ask a question. One moment for our first question. Our first question comes from James Shin from Wells Fargo. Your line is now open.
Hello?
Hi, James.
Can you hear me?
We can hear you. Yep.
Fantastic. Thanks for taking my question. I got a couple. Starting with the ALL, you mentioned obe-cel's expansion and persistence is and FELIX is tracking ALLCAR. I know it's still early, you know, follow-up's only 6.4 months for FELIX, but what are your thoughts on FELIX eventually or potentially matching the three year response rate we've seen in ALLCAR19? Secondly, for AUTO4, have you looked to see if there's some sort of co-stimulation component that may be helping responses given AUTO4 does not seem to be expanding in the periphery?
The first question is, the statement that I think, the latest statement that I made, that the product is tracking nicely also on persistence. The median follow-up on the 50 patients is about six months. Also when you then actually include, obviously the patients in the phase Ib cohort where we have about a median of a year or multiple more than a year at this point. There's actually quite a substantial amount of data that we do have in terms of persistence observation in patients over an extended period of time, not just, you know, for the three months, which is the minimum duration that we have in the interim analysis.
What we do see is that the curves tracks very nicely and obviously when you look at competitive programs, there is actually zero persistence at six months. By TCR and by flow, you lose the signal at three months. Even if, you know, if your observation is for six or nine months, for a good chunk of your patients, actually it will tell you already at that point in time that your persistence profile is very different. In fact, when we look at the curves that we have on median persistence from ALLCAR, we're tracking very nicely along that. That is kind of where we are with regards to the persistence.
In terms of predicting long-term outcome, long-term outcome is clearly, as we can see from the old CAR study linked to persistence, it's a prerequisite. I think what we're seeing is overall that we're starting to build, I think, a high level of confidence around the also from the FELIX phase Ib component of the FELIX study that indeed we do see a substantial proportion of the patients getting into long-term remissions. Obviously that requires full follow-up and update. I think we're starting to see, I think, get a good feel once we have all patients past one year of follow-up. It will take some time to actually get enough maturity into the dataset to sort of make that firm statement.
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. We could visualize that by doing IHC analysis, et cetera. So we can see the presence of the CAR T-cells. We see that they're expanded in that tissue. With that we know that it clearly is active at that space. Whether there's a co-stimulatory component, I think that's incredibly difficult to do is decipher. You know, you could probably do a bit of work on non-clinical 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 component. I'm not sure you can easily tease it out.
If I may, with just one more follow-up on CARPALL. For 1/22, what is the threshold for MRD negativity? Is it 10 to the minus five or minus six? I'm just trying to understand durability for MRD negativity. It looks like five out of 10 responders remained in MRD negative CR out to about nine months. Is this including the patients that received subsequent therapy? What is a good benchmark? I've been looking through Kymriah's durability for data, and I can't really find a good durability number for MRD negativity.
I think, James, I think first of all, The technical question first. The technical question is how is it done? This is, the assessment typically is done by, in those patients in the academic side, is done by TCR or by flow. The sensitivity that you have with TCR and flow is, you know, 10 to the minus four. You could push it a bit more, but it's sort of in that ballpark, in terms of the methodologies that are being used there. This is not based on NGS, not the way we're doing it in the pivotal study.
I see.
'Cause NGS is typically not available or is not available at all centers. Some centers have access to it, but some don't. That's the first sort of technical question. The second question is an interesting one because you're asking for 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. This is a Kymriah ineligible population. In short, there is no data available for these patients except that, you know, they're doing extremely poorly. For us to actually see them, you know, coming out at an 80% or 83% molecular CR rate is absolutely phenomenal.
You know, remember some of them were CD19 negative. The rest actually had with extramedullary disease. This is an incredibly difficult population. When you look at extramedullary disease patients versus normal ALL patients, you do see a decrease of about 50% in RRR usually in those patients. That's what you have to actually. That's the ball, the order of magnitude we're looking at. To see them come out at 80% is actually astonishing.
Thank you.
The short answer is there is no comparison in terms of data sets that we can look at. That makes, you know, and that sort of the fact that we see something that looks like Kymriah in a much better population is in of itself quite remarkable.
I appreciate the call, Christian.
Okay.
Thanks.
Thank you. One moment for our next question. Our next question comes from Matthew Phipps with William Blair. Your line is now open.
Hi, Christian. Congrats on the positive interim. Thanks for hosting the call. First off, for the FELIX interim, I assume all of these 50 patients were treated with fresh leukapheresis product. I remember it was almost a year ago, I think you guys switched to the fresh product.
Hey, Matt. Thanks for joining and really appreciate your joining the call. Yes, all patients, the manufacturing process is a fresh in, frozen out process. The reason for fresh in in this indication is that you have many patients with very high leukemic burden. 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 wanna freeze and thaw. Fresh in, this is actually why we went through a fresh in process for all patients.
Yeah. Okay. Thanks, Christian. You know, the press release does say CRS in this, you know, grade three or higher. Does that mean we should assume there was grade four or you're just putting grade three and higher as a kinda standardized practice?
I think it is, Matt, a lot to do with the fact it's a standardized practice. you know, the differences are, you know. There's big differences even within the grade threes and the grade fours. overall, I think what we can say is that all patients actually recovered very rapidly, and responded well just to the standard intervention that we have, for CRS and as well as for ICANS for that matter.
Okay. For AUTO1/22, I was curious if you had data yet on the persistence of those cells. Just kinda when you're seeing these relapses around nine months that are dual antigen positive, are they, you know, are you losing persistence of the CAR Ts or is there something else driving that?
What we're seeing in part we do see lots of persistence, which is what you would expect. you know, patients that actually had prior other CAR T therapy are known to actually show poor persistence. If you look at retreatment with Kymriah over time.
Mm-hmm.
there's a series of examples there. That's, that's I think one of the things you do expect. The second, is of course with patients that have, CD19 negative disease, that's basically only carried then on the CD22 side, and already have been exposed before to CAR T. Those clearly have a significant impact. 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, and I think that is sort of where you also would expect to see some impact. We do see, you know, an impact both on, loss of persistence.
What we do not see is we do not see target loss as a reason for relapse. 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? The answer is clearly yes, we do.
Yeah. Okay, last question. The updated runway guidance with the new capital, I guess, does that include or assume additional trials in NHL with obe-cel? You know, some expansions into maybe some of those specific cohorts.
It does include, obviously, you know, 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 obviously requirements for EMA as well as MHRA. There is obviously all the activity related to the manufacturing as well as commercial preparation. It also includes the startup of a non-Hodgkin's trial towards the end of 2023.
Okay, great. Thanks, Christian.
Okay, thanks Matt. Appreciate it.
Thank you. One moment for our next question. Our next question comes from Mara Goldstein from Mizuho Group. Your line is now open.
Oh, great. Thanks so much for taking the question. I just wanted to ask for a bit of just clarification on the obe-cel data in the ALLCAR study and the CLL PD patient where you had those unconfirmed MRD. Can you speak that those would begin to confirm? Just a follow-up question after that.
What we have is that we have molecular complete remissions that we see in the bone marrow. What we do see from an overall response assessment is we do it's categorized as a partial response because there's slightly enlarged lymph nodes, one or two in each one of the patients that we've picked up. The characteristics there is that it's just basically the diameter of the lymph node that you look at and not looking at the metabolic readout because the cells do not have an awful lot of metabolic activity. This is purely by size. What we see is that these PRs clearly are sustained over time. It's at this point, I think, difficult to tell whether these are PRs or should actually be reclassified.
At this point, we're carrying them as PRs, but with, from a bone marrow perspective, molecular complete remissions from bone marrow perspective.
Okay. All right. Thanks. That's helpful.
These are not unconfirmed MRD status.
Right.
This is confirmed MRD status, but they're PRs.
Okay. All right. Thank you. I appreciate that. Just on the manufacturing process for AUTO4, can you just discuss what the success rate of the sort of new process is versus the old process and whether you're seeing higher activity at lower doses given that you have higher memory T cells in there?
First off, in terms of our ability to manufacture for patients, we've actually been able to manufacture for all patients in this trial. We see differences here, where 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. 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. Just as it relates to Blackstone, you've received, those two milestones relative to, the current agreement. Can you just speak to what the next opportunity is from that, from that program?
Right. There is a total of $150 million project financing in the transaction. Of that, we have now actually received $120 million, $50 million up front, now 2x $35 million in milestones, so that's $120 million. There's at least $30 million as the last milestone, which is a regulatory milestone.
Okay. Thank you.
Thanks a lot, Mara.
Thank you. One moment for our next question. Our next question comes from Gil Blum, from Needham & Company. Your line is now open.
Hello, everyone, and congrats on the progress. Maybe I first one on the CRS and ICANS observed on the FELIX study. How do you feel these compare with current ALL therapeutics, and how do you think these are gonna be managed in the community?
Right. That's a good question. First off, when you look at how they compare, 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 four, Has about 13% high-grade ICANS, but about 60% of the patients with some form of ICANS. We're if you compare to that, we're at less than eight on high-grade ICANS and about, you know, less than 30% of ICANS all in of any grade. 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, you know, in the range of 26% high-grade cytokine release syndrome versus less than 4%, 35% high-grade ICANS with close to 90% ICANS of any grade versus less than 8% of high-grade ICANS. About a third of the patients experiencing or less than a third experience some form of ICANS with obe-cel. There's big differences there. When you look more carefully, and this is obviously on our side, it's a 92 patient data set. This is not a small data set we're talking about.
When we then look into, actually what's driving adverse events, there's clear relationship to tumor burden. What we do see is that patients with low tumor burden actually do even better. And I think that is actually what I think will ultimately become an important guide, is that the risk will be likely a guide 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. 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 from FELIX study and then up to, sort of a number of analyses that are ongoing in that regard.
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 tumor burden related, there is a good number of the patients out with blincyto that are actually managed in the hospitalized patient setting as well. Obviously, as with safety profile, we obviously have a very attractive opportunity here.
Thank you. That was very helpful. Long-term data from obe-cel, I found it was pretty interesting to see that CD19 negative relapses appear to happen earlier than the CD positive ones.
Mm-hmm.
For the most part. I find that as a surprising insight given, you know, 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. Clearly, you know, that clone either had to preexist or had 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 taken them out very, very quickly. In that regard, I think it's, you know. In terms of tumor mass, tumor mass removal happens within two weeks, pretty much. For the majority of your CD19 positive cells are gone in two weeks.
They either have and so 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 longer period of time, there's just so few in comparison, that it is just not that likely that you will get your mutational event that actually would give you that late CD19 negative relapse. I think that's the way probably I would look at it. It's a question of statistics and, you know, probability, frankly, of when that event actually has to occur to still actually be sorted out with the therapy as sort of your sorting device, to sort of look for these CD19 negative clones.
All right. The last question on T cell lymphoma. It's probably worth putting in context how difficult it is to get patients into long-term remissions.
Mm-hmm.
with standard of care. I don't think, when it comes to PTCL, it's usually refractory pretty quickly.
I think that's a really good point, Gil. It was interesting when we did the, our analyst call at EHA, when one of the experts from Memorial Sloan Kettering actually talked to us, and his statement basically was, "You don't get CRs at that stage of the disease." The fact we got CRs was already, in his view, remarkable. To actually then actually see these CRs actually survive and sort of be, you know, extend over nine to 12 months, I think gives us a lot of confidence in terms of the actual clinical activity that we're observing.
I think it's an excellent point, and it's certainly one of the real challenges that we have in that, at that stage of the disease, that any current elements of the standard of care doesn't actually give us complete remissions anymore. The actual key complete remissions that then actually can be sustaining these way that we just call into setting.
Maybe another relevant factor there is infection rates were actually not that high. It's another known issue.
That's true.
So.
Right. 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 was one of the design characteristics here, is to be able to hit the tumor without actually rendering the cells more immune suppressed, or the patients more immune suppressed. That, and that I think, looks very much that that actually is holding up and holding up over time.
All right. Thank you for taking all our questions, Chris. Thanks, and hold back.
Appreciate it, y'all.
Thank you. One moment for our next question. Our next question comes from Dev Prasad from Jefferies. Your line is now open.
Hi, this is Dev on for Kelly Shi at Jefferies. Just a couple of quick one. When can we expect to see that morphological cohort data? Will it be alongside the full FELIX data by mid mid-next year? Second is, now you are like what is the next program company it will be focusing following obe-cel? That's it for me. Thank you.
Thanks a lot, Dev. Thanks for joining. The first question is related to the morphological cohort. That obviously is the primary cohort we're looking at. The planned update, obviously for full data is ASCO. On the MRD cohort, which is the separate cohort that we're running, we're currently expecting that we have a first data update at ASH next year. That's the timing around there. With regards to the next program, obviously first of all, gotta get this program over the finishing line. That's gonna be where the primary focus will be for the business. As I indicated, we expect to add a non-Hodgkin's indication towards the end of next year.
obviously have significant opportunities between both AUTO1/22 as well as AUTO4. obviously we'll see how these programs progress and then actually we'll make the decisions accordingly. There are certainly interesting opportunities also with the pipeline that we're currently working on together with our academic collaborators. 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.
Thank you. Thank you for taking my questions.
Thanks a lot, Dave.
Thank you. One moment for our next question. Our next question comes from Eric Joseph from JP Morgan. Your line is now open.
Hi guys, this is Noah on for Eric. 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?
Yeah, really good question. Thanks a lot. Extramedullary disease patients actually are preexisting conditions, typically. It's very well described that patients, when you look at patient relapse antigen escape, so you have an elevated level of patients that have extramedullary disease, and that's true for other, you know, intensive therapies that we see in adult ALL. 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 at that point actually becomes much harder to treat.
As I indicated, quite often you see when you look at standard of care, different types of other therapies, that your objective response or the overall remission rates actually go down probably by about 60%, give or take, depending on the program you're looking at. 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. I think that's something we're gonna see. The level of these for these types of patients was less than some of the prior pre-pandemic trials.
I think what we are seeing in that trial is a consequence in part of the pandemic and that patients were kept on standard of care for as long as possible. And tried to avoid having to move them into hospitals or apparently have them travel across the country to join a clinical trial due to their immune suppressed status that they do have. And I think we are seeing a consequence of that with a higher percentage of patients with that sort of slightly [inaudible] state of the disease. We have to give the details on the percentages to this meaning [inaudible]. We'll sort of provide, obviously, a detailed update as well as the behavior of those patients, at the planned presentation at ASCO.
Great. Thank you.
Okay. Thanks a lot.
Thank you. I'm showing no further questions. This concludes today's conference call. Thank you for participating. You may now disconnect.