Autolus Therapeutics - Q2 2024

Transcript

Operator (participant)

Hello, ladies and gentlemen, and welcome to the Autolus Therapeutics Call to discuss its second quarter 2024 financial results and business updates. As a reminder, this conference call is being recorded. I would now like to turn this conference over to your host, Olivia Manser. Please go ahead.

Olivia Manser (Director of Investor Relations)

Thanks, Sean. Good morning or good afternoon, everyone, and thanks for joining us on today's call. With me today are Dr. Christian Itin, our Chief Executive Officer, and Rob Dolski, our Chief Financial Officer. On Slide 2, before we begin, I just want to remind you again that during today's call, we will make statements related to our business that are forward-looking under federal securities laws and the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These may include, but are not limited to, statements regarding the safety of clinical trials and development and/or regulatory timelines for our product candidates and our expectations regarding our cash runway. These statements are subject to a variety of risks and uncertainties that could cause actual results to differ materially from expectations and reflect our views only as of today.

We assume no obligation to update any such forward-looking statements. For a discussion of the material risks and uncertainties that could affect our actual results, please refer to the risks identified in today's press release and our SEC filings, both available on the investor section of our website. On Slide 3, you'll see the agenda for today's call. Christian's going to provide an overview of our operational highlights. Rob will then discuss the financial results before handing back to Christian to conclude and take Q and A. Over to you, Christian.

Christian Itin (CEO)

Thanks a lot, Olivia, and welcome everybody to our second quarter earnings call. A real pleasure to have you all on, and I'd like to start on slide number 4 with just a brief summary of the key highlights for the quarter. As you can imagine, we're in the process of going through the various review processes for obe-cel both in the U.S. as well as in Europe, and most recently now, also in the U.K. So that's been the primary focus from an operational perspective. I think we're making good progress and are on track with all the various interactions that we have with the regulatory authorities. The PDUFA target date, as you may remember, is November 16th this year, and we're tracking well towards that timeline.

We've also, obviously, initiated or have currently ongoing two phase I clinical trials. One is in pediatric ALL, which is a trial that is moving very nicely, and obviously, we're excited about applying and having obe-cel evaluated in pediatric patients, and that's ongoing. We'll report, obviously, in the upcoming periods on that trial. In addition, the phase I trial with patients that have an advanced stage, a relapsed/refractory stage of systemic lupus. This is the CARLYSLE study. We opened this study in the beginning of the year, and we dosed our first patient in the second quarter, and we continue enrollment in that study as we have projected.

More importantly, as we went through the course of the quarter, we did focus, obviously, very much on the update of the clinical data from our pivotal FELIX study, the phase II study that's underpinning the regulatory filings that we've made with the various authorities. Importantly, we looked at a number of aspects that we hadn't actually explored to the same extent in our prior publications and presentations about the program. One, of course, is to look for the longer-term outcome. And what we do see is that we do start to see a stabilization of both event-free survival as well as overall survival in the study.

We're starting to see a plateau forming, which is obviously something we've been very keen to evaluate, and we start seeing that now actually stabilize with more follow-up with the study. What was quite interesting, and I'll show you the data a little later as well, is that quite typically, what we have in this particular patient setting is that you actually look to consolidate the effect that you could induce a particular therapy to induce longer term outcome. Typically, what you do is you actually have the patients undergo a stem cell transplant when they are in complete remission, and ideally MRD negative, which was the case for all our patients.

What was quite surprising to see, and you'll see the data in a short while, as well, is that it didn't appear that the consolidation with the stem cell transplant improved the outcomes for the patients, which is very different from the other therapeutic options that are currently available in the space. We also, I think, had a closer look at the role of persistence into longer-term outcome, as well as the impact of bridging therapies, and particularly also the use of inotuzumab in patients that have very high tumor burden at time of inclusion, and where we did see a very effective approach here, in terms of bridging, with inotuzumab. Now, in terms of the operational side of the business and the governance side, we did strengthen our board.

We had Mike Bonney join as the new chair of the company, and Ravi Rao, who's an expert in autoimmune diseases and inflammatory diseases. So broadening of the skill set on the board and obviously a sort of a next step in terms of the evolution, both from a movement towards commercialization, which is obviously where Mike Bonney's background is, is obviously very strong, but also an expansion from a medical perspective into adjacent indications outside of oncology, which is clearly where Ravi Rao's particular experience is extremely valuable.

Now, in addition, obviously, we've been driving through a remarkable amount of growth and maturation of the organization, as we're setting up our commercial manufacturing capabilities, you know, getting through first regulatory filings and now keep pushing through that process, and are preparing for commercialization. There is a group of very talented leaders within the company that have really risen to the challenge and have done a fantastic job, and in recognition of their work and their leadership, have been promoted to senior vice presidents within the organization. This includes Brian, on the regulatory side, Chris Gray, Site Head for Stevenage, Markus Gruell on quality, Claudia Mercedes, really operations from the manufacturing technical operations side, but also actually in a broader role than that.

And then Dilip Patel, who's looking into market access and obviously did a fantastic job on that side as well. So great to see this group of leaders, really grow up and within the organization, and you know, having made substantial contributions that we expect to see a lot of important contributions going forward to the business. Moving to slide number 6, I would like to just briefly remind you of some of the key data that we did update on at ASCO as well as at EHA. Both meetings happened during the course of June this year. What we did focus on is actually look at the totality of the data from the FELIX study. And as you remember, the FELIX study has three cohorts.

By far, the largest cohort are the patients that have relapsed that are proper relapsed refractory disease with morphological disease, so more than 5% tumor burden, and this is the vast majority of the patients that we have treated. We have also had two small cohorts in addition that we have included in the study, a small cohort for patients that had isolated extramedullary disease. That's typically a cohort that actually gets excluded from clinical trials because of the difficult nature of the disease and the challenges of managing those patients. But also, a small cohort of patients that have minimal residual disease, so disease burden below five percent, but above ten to the minus three. So a very relatively narrow corridor of MRD, MRD positive disease. So that's the group.

We actually analyzed the totality of that data, and as you can see, this is a total of 127 infused patients. What we're starting to see is incredibly encouraging in terms of the patients that actually are in ongoing remission without subsequent stem cell transplant or other therapy. That is, I think, really important. We've got about 40% of the patients that actually continue in remission without any need for additional therapy. We also have this smaller subgroup that I'll also refer to now, the next slide, then, that received a subsequent stem cell transplant. There's 18 patients. They did receive this transplant while being in complete remission, not only in complete remission, but also being MRD negative, so no signs of measurable disease in these patients at the time of transplant.

And then obviously, we had also a group of patients that were moving to other therapies or have relapsed and died. So that's the status with a median follow-up of 21 months, which was the data cut that we were using for the ASCO and EHA presentations. Moving on, slide number 7, we're looking actually at the event-free survival of the patients. And as you can see, the event-free survival, and we're looking here at the two curves, with and without censoring for stem cell transplant. But both curves, you can see, are stabilizing and actually are starting to form a plateau, which is very indicative of a substantial portion of these patients remaining in continued remission, which is also extremely encouraging, in this very difficult group of patients who have a very aggressive form of disease.

When you see the curve actually for patients that had include the stem cell transplant, that's the green curve. The blue curve are the patients where we censor our patients that went on to stem cell transplant. What you see when you look at those two curves is actually a picture which is the opposite of what you would normally observe in these studies. Normally, we'd observe that patients that actually with stem cell transplant would do better and would actually give you a better event-free survival. What we're seeing here, it looks like the inverse, certainly not doing better, possibly doing a bit worse, if they actually receive the stem cell transplant after receiving obe-cel. Now, when we look at the on slide number 8 at the overall survival, we see a similar picture.

Certainly no evidence that a patient receiving a transplant provided them a survival benefit. And so very interesting in the sense that clearly the product on its own appears to be able to deliver a longer term outcome and may actually be able to serve as a standalone therapy for a subset of the patients. So these are two of the key findings that we were presenting at ASCO and EHA, which we move onto slide number 9. What we're evaluating there on the left-hand side is the impact of the of CAR T persistence in event-free survival in the patients. What you can see on the blue curve on the top are patients that had actually ongoing CAR T persistence, and you can see that these tend to do very well, again, with a stabilization of event-free survival.

Patients that lose CAR T presence at 12 months, you can see that's the median curve, the green curve, and patients that would lose CAR T persistence already at 6 months, it's the red curve, are tracking below. Indicating that indeed, longer persistence of the CAR T cells appears to be associated with a better performance on event-free survival. And just as a surrogate to look at, sort of the impact, we're looking at B-cell aplasia, and you can see also there the same type of stagger, but less differentiation between the patients. So persistence seems to be a better readout and a more reliable readout, if you want to understand the potential impact for longer term outcome. Now, in summary, on slide number 10, quick takeaways from this pooled analysis.

First of all, 40% of the responders are in ongoing remission without any subsequent therapy, and this is now with a median follow-up of 21.5 months. We clearly see evidence of a plateau forming, both in event-free survival as well as in overall survival. It does not appear that the stem cell transplant-based consolidation provides an advantage for the patients and does not appear to improve event-free survival or overall survival, which is certainly an important outcome consistent with the effects we're seeing, but certainly unusual in the field so far. Clearly, we do see an interesting correlation between ongoing persistence and improved event-free survival in these patients.

With that, what I'd like to do is actually move to sort of more the operational side, and so they're getting to commercial launch readiness, move to slide number 12. As you remember, we sort of, you know, have been already very active in the preparatory steps to get ready for commercialization for quite an extended period of time already. And a lot of that, obviously, was really focused on a key area of activities. Clearly it's the, you know, creating awareness around the medical affairs activities, as you would expect, building the value stories for the market access of the product. But then what's very involved is certainly the onboarding of the treatment centers.

And that onboarding process is very involved, not only from a company, but also from a center perspective. That's a real effort, that actually has to be put in, that goes across quite a wide range of activities that we need to sort of integrate in, whether it's related to apheresis, to the actual delivery of the product, the handling of the product at the center, as well as additional support that we're looking to provide both to the centers on this downstream to the to patients as well.

So it's quite an involved process, including everything related to the cell journey, from the collection of the cells at the center, to the manufacturing process and back, and the IT systems required to really be able to track the product and to ensure that we have a very clear chain of identity throughout the entirety of the process. So very substantial amount of work that's ongoing there. We're on track to have between 30 and 36 centers ready for activation by the time of an approval. And are gonna move once we are getting to that point, would expect to be within the first year of launch, at a level of about 60 centers, onboarded and active with the product.

So we're, we're moving here in a, in a very significant way, as well as, you know, at a, at a significant number of centers, even for the initial startup phase. Now, what we're particularly focusing on at where we are at this point in time, is really looking at the integration and the workings, and testing, frankly, of all the systems required to deliver the product. So there's a lot of activity going on, making sure that all the interfaces are working between the different processes, the different systems.

That's a very involved process that we're actually, you know, engaged in, in this, the third quarter and leading into the fourth quarter, to make sure that, all elements required to deliver this therapy are fully operational and tested out, and actually, have achieved the level of robustness required for a commercial operation. Now, on the next slide, it's just a brief view on kind of where we are and what some of those activities are that we actually need to think about, at the time point when we actually do get, to, an approval. Obviously, we talked about the path there on the prior slide. We eventually get to a point where hopefully around the target date, we do receive, an approval for the product.

Once that happens, there are several activities that need to take place. On our side, and driven from the company side, is really kind of the activities that are defined by the label itself, and there are certain aspects of training and activity that only can actually be finalized and run through at the time when the label is fully set and determine. That actually has to do with a set of trainings that have to be consistent, obviously, with the approved label, as well as obviously administering a REMS strategy and training that needs to actually be implemented at that point in time. So those are elements that, from a company perspective, you'll be able to complete once an approval is in.

Now, the centers themselves need to run through quite a range of activities at that point in time that really make sure that they're internally ready to be able to actually manage this type of a therapy, both from an administrator's perspective as well as from an actual physical, operational perspective. And you see quite a set of those activities that sort of will actually have to be worked through on the center and the inside of the center, and you can see that on the right-hand side spelled out in a bit more detail.

Now, when we think about what that means from an overall timing perspective, you can see the blue curve or blue arrow up there, is actually quite a range of time that we actually see where, from that time point where the center actually can get activated until it actually would enroll the first patient. And we will see certainly a variability among centers in terms of the time it will take to be on board and be enrolling patients. To look at that in a bit more detail, we will go to the next slide and just look at sort of in a relatively simple way of what are some of those key activities and timelines.

Completing the site accreditation, we expect will take anywhere from two to 12 weeks with the centers that we have prepared for the through the onboarding process. But are now from the time point where you can actually in initiate the site activation will have take anywhere between two and 12 weeks. Obviously patient screening, leukapheresis, scheduled, and having that completed anywhere from 1-2 weeks at that point in time, and then obviously the anticipated vein-to-vein delivery time of 16 days. So when you think about that, and you think about a target date, a PDUFA target date of middle of November, and as well as sort of year-end holidays, it is reasonable to assume that the first patient dose will be happening in the early part of 2025 if we're operating on those timelines.

So I think that sort of, I think, hopefully gives you a sense for what it means to start up, and what are sort of reasonable assumptions around when to expect kinda first patient's dose, and then obviously it would gear up from there as we go through the course of the year. Now, with that, what I'd like to do is switch gears and just briefly talk about sort of the obe-cel product family on Slide 16, franchise opportunity. This is a slide you've seen before. Obviously, we've continued to work not only on the current activity in on the adult ALL side, but also are working on the pediatric side as well as the autoimmune side with obe-cel. And we'll continue to actually work on AUTO1/22 as well as AUTO8.

AUTO1/22, mostly on the pediatric ALL side, where we do additional work with the UCLH and GOSH, our partners for that program for a long period of time. And we're also, obviously with AUTO8, continue to work on the multiple myeloma side, but we're also looking to sort of expand the opportunity for that program going forward as well, and we'll update you as we go, as we go forward and initiate next studies with that program, when that actually happens. So with that, just a quick word on the environment on the autoimmune side of this space that many of you have watched very carefully. We had one major conference that happened in Q2, which was the EULAR conference.

Interesting data set presented during the course of the conference. I think what we're starting to see is some differences that appear between programs. Still early days in terms of understanding what is contributing to some of the differences that are being observed, to what extent are those product driven, to what extent are those factor variability in the patients that are being treated. But certainly very interesting development that we're seeing, but also overall, I think also very nice corroboration of the initial observations that we have seen with Georg Schett in Erlangen, that indeed there is very profound impact that can be had in those patients using CAR T approaches.

When we look at the next slide, just to remind you, obviously, that we have a program that has a remarkable set of similarity in terms of the clinical properties to the program that's used in Erlangen. But also, not only do we have a high degree of similarity in terms of the efficacy, the persistence on the pediatric ALL side, where we can compare the programs directly, but also, obviously, we do have a very substantial amount of safety data, and which also is an area where we can see differentiation to the program in Erlangen, but also differentiation to any of the other CAR T programs that are currently commercially available.

And what you see is just a summary there on the right, on the table, on the various key outcomes that we have seen across the various studies that we've conducted with obe-cel. And I think gives you a very good view on the level of activity that we're seeing and the ability to achieve those levels of activity with a very attractive safety profile. Now, the study on Slide 19, the CAR-SLE study, our phase I study in SLE, as I indicated, the study, obviously, start up happened during the latter part of Q1 and into Q2. First patient dosed in Q2, and we're continuing to enroll in the study.

We're planning 6 patients at a 50 million cell dose level, which also is a level that we know to be highly active in pediatric ALL, giving us molecular complete responses. And also a level of dose that is also highly active in the adult patient population, where, as a reminder, we're using as little as 10 million cells to induce complete remissions in patients with high tumor burden in that setting. So overall, I think we're in a very interesting stage. We're starting to sort of get first insights from a data perspective, and we'll also continue to collect that data with a plan to have an additional update on clinical data later in the year.

Now, other pipeline programs on Slide 21, as you remember, there's a number of other programs we're working on. I think, with regards to, Autoimmune, I already indicated that, we're looking at, potentially expanding the program, into additional indications. So that's something that's ongoing. And we'll update, certainly by the end of the year or the next year on sort of the trajectory we're gonna be on. And then just as a quick highlight, because we haven't actually talked about that in a while, is AUTO6NG. That program also, obviously, is enrolling patients, and first patient actually has been treated as well in the second quarter, and as part of the progress that we were, making during the quarter.

Overall, progressing well, and we also expect additional publications to come out during the second half of the year related to our clinical programs that we've been conducting. With that, I'd like to hand over to Rob, who will then lead you through the financial results.

Rob Dolski (CFO)

Thanks, Christian, and good morning or good afternoon to everyone. It's my pleasure to review our financial results for the second quarter of 2024. I am on Slide 23, where we see at the top, our cash and cash equivalents at the end of June 2024, total $705.9 million. That's compared to $239.6 million at the end of last year, December 31. Our total net operating expenses for the three months ended June 30, 2024, were $58.9 million, as compared to $44.4 million for the same period of 2023. For research and development, these expenses increased from $33.2 million to $36.6 million for the three months ending June 30, 2024, compared to the same period in 2023.

This change was primarily driven by increases in operating costs related to our new manufacturing facility, employee salaries and related costs, and obe-cel clinical trial and manufacturing costs. These were partially offset by a more favorable U.K. R&D tax credit reimbursement for the period as well. General administrative expenses increased from $11.1 million to $21.9 million for the three months ending June 30, 2024, compared to the same period last year. This increase was primarily due to salaries and other employment-related costs, driven by increased headcount supporting our overall pre-commercialization activities. Finally, for the company, net loss was $58.3 million for the three months ending June 30, compared to $45.6 million for the same period in 2023.

Autolus estimates that with its current cash and cash equivalents, we are well capitalized to drive the full launch and commercialization of obe-cel in relapsed refractory adult ALL, as well as to advance its pipeline development plans, including runway to data in the first pivotal study of obe-cel in autoimmune disease. I'll now hand things back to Christian to wrap up with a brief outlook on milestones. Christian? Okay, I'll jump in here. We're waiting for Christian. Maybe moving to Slide 25. Just again, to hit on some of the anticipated milestones through the year-end. We've got the target action date on the FDA side with the PDUFA. As Christian mentioned, that's November 16th, 2024. And we'll have updates certainly at the end of ASH. You've seen some of those, with the ASCO data and EHA.

That'll be further advanced, and presented towards the end of the year. And then, as Christian mentioned, on the SLE phase I study, we expect initial data from that, that program later in the year.

Christian Itin (CEO)

So Rob, thanks a lot for jumping in. My headset was basically giving up. So what I actually wanted to say, in addition to the news flow, is really that we're going to be obviously laser focused on getting the program through the registration to first approval. And getting the launch off the ground with the product. That will be the primary focus of the company. Looking forward to the data update, absolutely, but operationally, that is what we're really gonna be having our eye on. And we're looking forward to keeping you updated on the progress there. And now we're happy to actually go into Q and A.

Operator (participant)

Thank you. At this time, we will conduct a question and answer session. As a reminder, to ask a question, you'll need to press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q and A roster. Our first question comes from Gil Blum with Needham & Company.

Gil Blum (Senior Analyst)

Hi, good morning, everyone, and thanks for taking our question. So, first one, as it relates to the launch, it, I'm sensing here maybe something of a rolling launch. Would we see sites coming on, you know, you know, over time, basically?

Christian Itin (CEO)

Hi, Gil. That's actually not what it is. What we're trying to do is just explain that the actual activation at the centers is ultimately a decision or frankly, a process that's governed by the centers. And the timeline that we're seeing, you know, anywhere from about two weeks to 12 weeks, is pretty much what we see across the space with centers that are ready to actually get activated and then the actual time of activation. A lot of time it is actually also driven in the centers by frankly, patients that are in need of therapy, and that usually actually accelerates the process and the final stretch of the activation. This is not a rolling launch by any stretch of the imagination.

Being able to be out of the gate, you have 30 to 36 centers ready to activate at that point, which has been all, you know, the internal part at the centers, that compares very favorably to almost all launches that actually have been done in our space. Could you go from there to 60 centers within a year, will give us more than 90% access - patient access, in this indication, which is obviously a very, very rapid build, much more rapid than I think we've seen across the, across the competitive programs.

Gil Blum (Senior Analyst)

Thank you for the clarification. And maybe.

Christian Itin (CEO)

Thank you.

Gil Blum (Senior Analyst)

Moving to the autoimmune data. So probably the top question is what level of data disclosure should we expect at the center? And are we talking mostly safety, or will there be some follow-up to suggest that efficacy as well?

Christian Itin (CEO)

I think that most of the update will clearly be on safety and short-term impact, or shorter-term impact of the therapy. As I indicated, we treated the first patient in Q2, so that gives you the max of observation time that you will have. And obviously, the rest of the patients will be at a shorter time period than obviously a Q2 to end of the year timeline. So there's gonna be, you know, initial data that will indicate activity, but obviously will not be a substantial amount of follow-up yet on most of the patients.

Gil Blum (Senior Analyst)

Okay. And maybe a bit of a in the weeds question. So we saw data updates for CAR Ts that include 4-1BB co-stim versus CD28 co-stim. And, you know, historically, people have talked about how CD28 tends to, you know, have very high ramp up in cells, but also leads to maybe higher toxicities, and 4-1BB can lead to, you know, really long aplasia. Maybe there are AIDs, you know, autoimmune indications that are more amenable to one versus the other. Kind of probing your thoughts here.

Christian Itin (CEO)

So what you're basically referring to is that the costimulatory domain has sort of a impact on the initial activity that we see, of the cells, and particularly the cell expansion of the CAR T cells that we're seeing. And that is certainly been generically true. You know, most programs which show a faster onset of proliferation of the CAR Ts with the CD28 is somewhat slower in 4-1BB, but then 4-1BB would give you longer persistence, and the CD28 typically gives you very little persistence. And that obviously then has an impact, obviously, on the longer term, you know, B-cell aplasia, et cetera, you'd see, because you frankly, in one case, you have no activation, the other case, you have activation.

What I think is worthwhile remembering, certainly for obe-cel, is that actually the peak expansion that we're seeing with our product exceeds that of the CD28 CAR. Okay? So the story certainly is a bit more complex than just co-stimulation. So we actually see, have an excess level of in terms of of maximal expansion of the CAR Ts, which are beyond of what the CD28 CARs were able to do, and that combines in addition with a very long persistence. So that gives you a very, you know, I think, unique set of properties that we do have with obe-cel that is quite different from the rest of the commercially available CAR T programs.

Now, in terms of the type of activity you may need, depending on the indication, that's an interesting question, and I think I would probably answer it from the position of what is the mechanism of action. The mechanism of action, obviously, that we have is the removal of B-cells, CD19-positive cells, and also plasmablasts. In the case of autoimmune disease, what you have to get rid of typically are clones of cells that actually drive the autoreactive antibodies. So you need to actually have a complete depletion of those cells if you want to get to a reset of the disease, and that I think sort of should be the expected outcome for a CAR T therapy, which is obviously a very modal therapy for this type of a disease.

So that mechanism is shared across the board, and I think what we need to ask then is, what are the properties that we need to have to achieve that goal? In my view, what you need to have is, because it's a cell-based mechanism, you obviously need to have an ability to actually have proper cell-cell engagements. In other words, your CAR T-cells have to find those particular cells that drive autoimmunity, and then actually have to be able to take them out. Because it's a cell-based process, you need to have to go through cell migration, distribution, et cetera, to do that, and you need to get all of those cells eliminated to have that ability to drive the autoimmune reaction. And that means there's a certain amount of time required to actually do that.

What we do not know is, we do not know what's the minimal amount of time to actually achieve that goal. What we do know is that the time that actually the program had in the Erlangen study was sufficient to do that. So the importance of the message that I was looking to give before in the prepared remarks was that our product actually shares all of those properties in terms of presence, depth of coupling to the B-cell compartment, and sufficient persistence to actually achieve that goal, shares that with the Erlangen program, but has a better safety profile. So that's, I think, the way I would answer the question.

How short you can go, that's frankly a thing that none of us knows at this point, because we haven't seen enough data from other programs with different profiles from the Erlangen product, to get a feel whether something else might also work. But what we do know is that that profile that we have seen in Erlangen does work.

Gil Blum (Senior Analyst)

All right. That's very helpful, Christian, and thanks for taking our questions today.

Christian Itin (CEO)

Thanks a lot, Gil.

Operator (participant)

One moment for our next question. Our next question comes from Asthika with Truist.

Asthika Goonewardene (Managing Director and Senior Biotech Analyst)

Hi, good morning. Good afternoon, guys. Thank you for taking the question. So congrats on the progress as well, Christian. I'm gonna add on to Gil's questions on the centers here, and then maybe ask something related here. Among the 60 centers targeted, how many centers require an approval in hand to even begin the qualification process? And just to give some color here, all in, how long does it take for a center to become an ATC, including the whole qualification process and site activation required? And then I got a couple of quick follow-ups.

Christian Itin (CEO)

So there's sort of, you know, two steps to that. First of all, the center has to be, you know, obviously interested to actually onboard the product. That's the first step we have to take. We had remarkable success in, you know, having the centers interested in actually taking the product on board, hence the, you know, very bullish guidance that we're giving of 30 to 36 centers ready to be activated at time of approval. So that's a very significant involvement. Just to put that in numbers, that is, those, you know, the centers do cover about 65%-70% of the ALL population in the U.S. So that's the magnitude we're talking about, and that's right out of the gate.

So that's, you know, the level of interest to actually even engage. That's the first key thing you need to do. The second is, you need to actually go through all the preparatory steps, so that you can get, when you get to the label, you can actually activate the center. That can take anywhere from 6 to 12 months. So that is a very involved process that, you know, has a lot to do on the IT side. There's contractual pieces that you have to put in place, and so on. So it's a very involved process and typically takes in that order of magnitude of 6 to 12 months. This is why we've been working on this for an extended period of time.

Many of the centers that we expect to get ready for activation after an approval is in are already now in the onboarding process, just to be clear. So that's a continuous process, and most of these centers actually are ongoing in terms of process already at this stage. So those are kind of the key things. But then the final bit is, obviously, you know, we can go with these 36 centers as far as we want to go, but there are, obviously, the final steps do require the actual label in hand. And that is sort of the final, that final step that actually gets you to that into that, you know, between two weeks and 12 weeks max, time to actually get the centers fully activated and enrolling patients.

So that's sort of that, that stretch. And obviously, the vast majority of the centers we're working with, obviously, have made the decision to actually put all the work into the onboarding process ahead of actually having the label in hand. There's some, obviously, that would actually want to wait until the label is there and would sort of actually engage the higher workload of the activity later on. But those obviously will be beyond the 36 centers and will be at that end. But the overall majority of the centers actually have been, you know, remarkably engaged and willing to actually proactively work on the activation.

Asthika Goonewardene (Managing Director and Senior Biotech Analyst)

Thank you, Christian. That's really helpful. Then maybe bigger picture, with the recent deal with BioNTech and the raise, you know, you've got a good, nice pot of cash that you can kind of dispense for clinical development here. We see a lot of, obviously, a lot of prioritization done for commercializing obe-cel as well as doing the autoimmune study. Maybe we can, this is a good time to also revisit what comes next. What's next on your really high on the priority list after these two top two priority items?

Christian Itin (CEO)

Right. So look, we're very keen, obviously, on sort of, you know, committing to the next clinical study. So this is, you know, very much, a workflow that is in full swing at the company. Obviously, at the same time, we would not want to distract from what we need to do now, which is a very heavy lift for any organization going through the first time through an approval and a launch. So, we want to be mindful that, you know, on the one hand, that we're having the focus required to execute, and execute with what we hope to be a best-in-class launch. At the same time, obviously, we're preparing for that, for that significant engagement and, into the next clinical study. So that's what we're working on.

And we'll obviously update, you know, the, you know, from a public perspective, you know, at the right time around that. But that's obviously where there's a lot of activity in. We're also very excited about the interaction we're having with BioNTech. There's, you know, really, you know, great chemistry between the teams. A lot of good engagement, and broader discussions that are going on. And I think that sort of obviously has, you know, sort of key activity that is obviously doesn't have yet that level of visibility in terms of news flow, but, it's an area we're very excited about, and I think will create additional opportunities as well, that are not, necessarily, visible at this point from a, an overall company perspective.

So I'm excited about those next steps, but first things first, you know, get the approval, get the launch off the ground, get into the next pivotal study, and then we're gonna move from there. But very excited about kind of what the end of the year and then also the next year will bring.

Asthika Goonewardene (Managing Director and Senior Biotech Analyst)

Great. Thank you so much for taking my question.

Christian Itin (CEO)

Thanks a lot.

Operator (participant)

One moment for our next question. Our next question comes from Kelly Shi with Jefferies.

Kelly Shi (SVP and Senior Equity Analyst in Biotech)

Hi, congrats on the progress, and thanks for taking my questions. As we are very close to the first launch for Autolus, curious, just a quick question, maybe like, it's too early to comment on the price of obe-cel, but curiously, if the split dosing regimen would add additional cost compared to single dose of cell therapy?

Christian Itin (CEO)

Hi, Kelly. Really good question. So first of all, obviously, on price, you're right, that would be too early to actually give any specific guidance. I think we can only remind sort of the current price levels that we see with Tecartus, which is around $462,000 in the U.S., and Kymriah, which is around $582,000. There is an overlap. There's also an age range, where, you know, FELIX study, one study goes from 18 years onwards. When you look at the labels for the two commercial products, one obviously goes up to 25 years, which is Kymriah, and the second one, Tecartus, goes above 25 and older. So, that's sort of the range that's currently in the market.

I think we can give more guidance than that and just actually, you know, basically, point to the reference prices that we have here in the space. In terms of the cost, or the added cost related to dosing, what we do obviously with obe-cel is we do a tumor burden adjusted dosing. And that actually has proven to give us an enormous amount of robustness in terms of the safety data, which is driven on the one hand by the design, but also takes into account, obviously the tumor burden. And remember, these are very particularly the older patients, tend to be fairly frail patients, and a lot of these patients certainly cause a lot of issues with early CAR T programs, lead to actually treatment-related mortality.

We've seen that in some of the real-world data as well, that being a real issue. And, as you may remember, our median age in the study actually was about 10 years older than some of the other studies that were done in the space. And despite we did that whole thing through the pandemic, which also aggravated a lot of the safety-related challenges further. So the dosing that we have in combination with obviously the profile, gives us a very substantially improved safety profile. The primary cost that actually you see for the delivery of the CAR T is not the delivery itself, it's not the administration, because that's pretty uneventful. That's literally an infusion, and that's that, and that tend to be very short infusions. We're talking maybe 15 minutes or something like that. So it's a very short infusion.

That doesn't actually add a significant amount of burden. What actually adds burden and what really drives cost is related to the management of the patients, where they actually do experience high-grade CRS or they experience high-grade ICANS. And in fact, the ICANS are almost worse because they tend to take a substantially longer period of time to actually get under control, and obviously often are associated also with long-term steroid use, and the combination can lead to sepsis and treatment-related mortality. So that's where the real cost actually comes in.

To be able to reduce the number of events massively, but also shorten the recovery time, which is both elements we've seen with obe-cel in the FELIX study, actually reduces massively the cost and is actually one of the key attractive elements for onboarding the product, which is that the product actually will be less intense to manage. Because it's less intense to manage, actually, the profitability goes up for the centers.

And that actually is one of the key drivers, that from a financial perspective, is attractive for the centers, why the onboarding also is going as well as it does, and what is also recognized not just as a clinical, improvement as well as a longer-term outcome, but also an immediate financial improvement, that, I think is visible and, quite well understood within the centers that we're engaging with.

Kelly Shi (SVP and Senior Equity Analyst in Biotech)

Super helpful, and thanks very much. And also have a follow-up on autoimmune, follow your comments from opening remark. So although we saw better tolerability of CD19 CAR T cell therapy in autoimmune indications when compared to hem/onc trials from Dr. Schett's pioneer work, we started seeing neurotox from other ongoing trials in lupus. So curious if you could share your insights on if the patient baseline difference as more like a dominating factor or CAR design or maybe other reasons regarding the impact on safety. And also another important question here is, how obe-cel achieved much better neurotox control in the hem/onc oncology indications generally speaking, and also whether this is transferable to autoimmune trials in your opinion? Thank you very much.

Christian Itin (CEO)

Yeah, very good question, Kelly. So what we're also seeing is, in general, what we're seeing is that there's several parameters that drive immunological toxicity, and this is both actually CRS and neurotox. And the parameters on the one hand are the number of target cells that, you know, have to be taken out, have to be removed. Obviously, that means that defines the number of CAR T cells that get activated, and with that, depending on the design of the CAR T cells, gives you a base level of activity, potential cytokine release, and also the risk of immunological toxicity. So that's one element, so it's the number of cells.

Now, when we look at the neurological at the autoimmune indications, we do not expect to see significant variation in terms of the number of cells that have to be removed. These are patients that have overall normal immune system. They have, are lucky in the sense that they have individual clones that recognize structures in the body and drive autoimmunity as a consequence of it, but it is not a proliferative disease as we would see in lymphoma or leukemia. So we see a pretty steady level of pretty much a normal level of B-cells and plasmablasts that need to be removed. So that sort of basically becomes a constant. But then actually it becomes a variable, and that's the second element that can drive toxicity, is really the design of the CAR T product.

The two key components there, we already talked, and I think, Asthika was mentioning that before, which is the, the costimulatory, elements and the impact that the costimulatory elements can have. They do have an impact in terms of how quickly, the cells proliferate and how much cytokine release they naturally do. That's an element that is sort of in part, coming from the costimulatory domain. But what we have proven with, obe-cel is really that the primary driver, and probably the most important parameter, that we're dealing with, is actually the way that the CAR T cells physically engages with the target cell.

And what you do remember about the design of obe-cel is what we're looking to do with obe-cel is create a product that behaves as physiological as possible, while obviously being a chimeric antigen receptor, but trying to be as close to a normal T-cell engagement. And what's characteristic for a normal T-cell engagement is that the engagement is short-lived. So a T cell actually recognizes the target cell, forms the synapse, delivers the cytotoxic content, which drives the cell death or apoptotic process in the target cell, and then actually disengages rapidly. We're talking minutes in terms of the engagement max. And that short engagement is really characteristic of a normal physiological engagement.

It is that engagement that actually is clearly different for the first generation of CD19 CAR T programs in the space, but also will be true for most of the products currently being developed for autoimmune diseases. That is that most of those designs use antibodies, fragments to CD19, that are high affinity in nature, which means they have a fast on rate and a very slow off rate. Net, net, if you then think about thousands of CARs on the side of the CAR T cell, thousands of CD19 molecules on the target, on the target cell, gives you basically an enormous amount of high affinity interactions between the cell and very, very long interactions between them. Now, those low, long interactions do not actually help the kill. That already happens within a minute or so.

But what they do is they drive an overactivation of the CAR T cell. That overactivation drives the cytokine release, as well as actually drives exhaustion of the cells, and ultimately is really contributing in a very significant way to toxicity, and that toxicity is unrelated and unnecessary to get the activity. And so what we designed with obe-cel is really obviously a product that has the ability to be specific, but disengage rapidly after delivering the kill, and we do that by having about 100-fold faster off rate from the target than any of the other products out there. And that gives us a very different behavior of the CAR T cell and fundamentally changes the toxicity profile. That difference will be relevant in any setting, and will give you a substantially better safety profile in any setting you would actually apply the CAR T cell.

Kelly Shi (SVP and Senior Equity Analyst in Biotech)

Really appreciate your insights. Thanks, Christian.

Christian Itin (CEO)

Thanks a lot, Kelly.

Operator (participant)

One moment for our next question. Our next question comes from James Shin with Deutsche Bank.

James Shin (Director of Biopharma Equity Research)

Hi, good morning, guys. I had a question on the onboarding activity. The range of two to 12 weeks for accreditation, are the sites that would fall into the two week range centers that have existing CAR T programs, and those that fall in the 12-week range are centers that are CAR T naive? That's question number 1, and I have a follow-up.

Christian Itin (CEO)

Okay. Hi, hi, James. Good, good, good way of thinking about it. It's suggested that that could be the case, but I don't think actually that's true. I think it has a lot more to do with the workflow at the centers. There are currently probably 4 to 5 programs for many of the centers that they're onboarding. So there's a very involved process for many of the centers, so there's a capacity component. And I think ultimately, we'll be very much driven by frankly, patient need as well. So I think that's gonna be a big driver of actually how quickly that final stretch on the activation will occur. So I think there's a lot more to do with that. Most of these centers, obviously, are active CAR T centers. You know, we're talking about the top centers in the U.S., which, you know, frankly, all of them have tend to have multiple CAR T programs already on board.

James Shin (Director of Biopharma Equity Research)

Appreciate that. And then on the P&L side, are we pretty much at full commercial run rate for the commercial activity? On the spend side, that is.

Rob Dolski (CFO)

Hi, James. It's Rob. Yeah, so we are still gonna be building towards the end of the year. We haven't fully built out the team yet in the U.S., so I wouldn't necessarily project kind of, you know, a flat run rate from Q2.

James Shin (Director of Biopharma Equity Research)

Thank you very much.

Christian Itin (CEO)

Thanks a lot, James.

Operator (participant)

One moment for our next question. Our next question comes from Matthew Phipps with William Blair.

Matthew Phipps (Group Head and Biotech Equity Research Analyst)

Hey, Christian. Thanks for the update and taking my questions. Following on a little bit with what Kelly asked on earlier, but with Cabaletta reporting a grade four ICANS this morning from their Lupus trial. They said they're implementing some protocol modifications, including some seizure prophylaxis. Wondering if that's something that you guys have used or thought about using? And then I realize you are very early in your trial for me, but maybe you can just give any kind of comment on how the safety profile is reflecting the, you know, kind of FELIX and other experience with obe-cel so far.

Christian Itin (CEO)

Yeah, good to have you on, Matt, and thanks for the question. So I think probably the best surrogate here, obviously, we're, you know, as I indicated, we're early on in our phase I study, so you know, not seeing something in in that early stage doesn't really, you know, get you sort of give you a clear-cut answer. So I think the better part of looking at it, a better way of looking at it, is really in the ALLCAR19 extension part of the study, where we had about 40 patients with various forms of non-Hodgkin lymphoma.

What we did observe in those patients is that without prophylaxis, so just normal, you know, conditioning and dosing, and prophylaxis, and also no steroid prophylaxis and no seizure prophylaxis in these patients, we actually did not observe neurological toxicities in these patients. So we didn't observe the ICANS in these patients, which I think is giving us a lot of confidence around the overall product property. And similarly, obviously, patients with low disease burden in ALL also had a very limited neurological activity, and in fact, no Grade 3s even in those settings. So overall, I think the product profile is obviously what really is different here, for obe-cel.

What we know from our product is that, clearly, that we do have a different behavior that we're seeing. And, you know, we're based on the non-Hodgkin's data, which is probably, you know, a good way of sort of comparing, although we do have, obviously, localized high tumor burden in these patients. There's not a lot of, you know, bone marrow burden tends to be very low or normal and normal circulating B cells, that in that setting, obviously, we have not seen neurological toxicity in the patient. So it gives us a lot of confidence that we are, obviously in a good space. But, you know, well, it's early days in autoimmune, and I think there's a lot to be learned.

Matthew Phipps (Group Head and Biotech Equity Research Analyst)

Great. One quick follow-up. I don't think you discussed this, so. But, when do we get an announcement on, I guess, the next autoimmune disease beyond lupus that you guys might explore?

Christian Itin (CEO)

I think we're, you know, obviously, we're gonna go through kind of the launch process. I think, you know, kind of the next trajectory and update, we're probably gonna provide in Q1, in terms of next steps. And, you know, that's sort of what we're working towards. But at this point, we're keeping the focus where we think it needs to be, which is really on getting through the regulatory process and getting, you know, into its way into the launch, before we're diverting, in a broader way, diverting focus.

Matthew Phipps (Group Head and Biotech Equity Research Analyst)

Great. Thanks, Christian.

Christian Itin (CEO)

Thanks a lot.

Operator (participant)

One moment for our next question. Our next question comes from Yanan Zhu with Wells Fargo.

Yanan Zhu (Senior Equity Research Analyst)

Great, thanks for taking our questions. On the autoimmune side, I was wondering, you mentioned the three centers are enrolling in U.K. and Spain. I'm just wondering, are all these centers also FELIX centers? And have you enrolled patients, SLE patients at all of the three centers? The other question related to autoimmune is wondering about your thoughts on the recent Cell publication regarding allogeneic CAR T and demonstrating some efficacy in some autoimmune indications. Like, as you look into that data, what is the learnings and takeaways regarding the prospects of allo CAR T in autoimmune? Thanks.

Christian Itin (CEO)

Thanks, Yanan. First off, with regards to the centers, the answer is all three centers have been FELIX centers. And so there's experience in all centers, and they're all enrolling. So that's, I think, the first part of the question. The second part of the question was related to just different modalities that could be giving you deep, sort of deep remission or deep responses in the B-cell and plasmablast compartment. Obviously, there's sort of three basic categories that are sort of under investigation. You have the autologous CAR T-cells, which is what we talked about mostly on the call.

We have allogeneic CAR T cells, which is what the question is, and then also there are bispecific T-cell engagers, which are sort of the three categories of at least T-cell mediated approaches to reset the B-cell compartment. What we do know at this point is obviously that with the autologous programs, that we do get very deep responses. You know, if you look at, obviously the original data in ALL, and I think indicative that we can get to transformational outcomes. What we know in pediatric ALL or in adult ALL, is we can get extremely deep responses being, you know, MRD negative at a level of beyond the ten to the minus six.

It is the most stringent way you can test it, and the ultimate test is get patients in long-term remission in those settings, which obviously is what we have seen with our product and what we've seen with Kymriah in pediatric ALL as well. So clearly those are probably the most stringent tests you can run to evaluate the activity of these products. We do know that the allogeneic programs can, you know, make a cut into the compartment. You know, to date, all the data we have on the oncology side is indicative of the fact that the cut isn't as deep or as consistent. And I think that is certainly going to be true, I think also in the autoimmune setting.

But you do expect that when you do make a cut in the compartment, that you see an impact. And even if you do even much less of a cut, as we've seen in the compassionate use work with Blincyto in the trials that were published earlier in the year, you could see that actually, at least temporarily, you could actually have a reduction of B-cell counts in those patients and see an improvement, a clinical improvement in those patients. It doesn't appear to be actually sustainable, but you would see an improvement. So I think what we've seen so far is consistent with what we know, what these products can do.

The fundamental question is going to be: Is there gonna be a differentiation between, T-cell engagers and allogeneic programs? And do either one of them is actually, get you to a place where you can get a sustained outcome? And I think we just don't know at this point in time. I think we have a really pretty good feel that the autologous programs, if any, will have probably the best, chance of actually giving you a transformational outcome. I think that's sort of where we are at this point. Obviously, it'd be interesting to see how, you know, these other programs evolve over time. And, we certainly will be, carefully watching the space.

Yanan Zhu (Senior Equity Research Analyst)

Great. On the oncology side, I was just wondering about your confidence about delivering the 16-day vein-to-delivery time and also your sense of manufacturing failure rate, and how do these compare with Tecartus's? Because that's something when we talk to some experts, these aspects of reliable delivery seems to be one of the factors that could drive the shift from one product to the other. Thanks.

Christian Itin (CEO)

Yeah, really good question. So, you know, this is a patient population we're in, where you need to deliver. You need the therapy to actually be delivered. These patients don't have extra time. There's not a redo typically possible, so you have to have very high levels of reliability of the delivery. What we're able to show in our clinical study, if you compare to the clinical studies with each other and, you know, remind you, we did ours through the pandemic with a lot of limitations. We actually have a higher intent to treat, we have actually a higher level of intent to treat than we've seen in the prior study, around 84%, and that clearly was a very good outcome overall on intent to treat.

So we can show. We can look at it from that perspective. We can look at it from the perspective of the, you know, out-of-spec range, which is around 6% in the FELIX study, which is very low, and we're at 21 days across the FELIX study. And one of the things that we have included and sort of implemented through the course of the FELIX study is a set of faster analytical methods that would allow, actually allowed us to accelerate the release of the product. So a big chunk of the time you actually have in your delivery time is not your manufacturer, but it is actually the analytical testing and to sort of achieve the release. And then the final part is related to the logistics.

And one of the things that we're doing, we're implementing for the commercial delivery, this is part of the collaboration, the deal that we have with Cardinal Health, is that we are shipping product before the release is completed to the U.S., so that the product is already close to the site. It's in our custody, and will then actually be released once the product release is through. But what that does is, it basically takes that element of the turnaround time out of the equation. So between the logistics element as well as the faster analytics, we'll be able to cut about six days out of the arranged delivery time. So what we're guiding is currently 16 days at time of launch, with an opportunity to reduce, and that time is pretty much in line with what the best competitive data looks like today.

Yanan Zhu (Senior Equity Research Analyst)

Very helpful. Thanks. Thanks, Christian.

Christian Itin (CEO)

Thanks a lot, Yanan.

Operator (participant)

One moment for our next question. Our next question comes from Sebastian Van der Schuit with Van Lanschot Kempen.

Chiara Montironi (Biotech Equity Research Analyst)

Hi, team. This is Chiara Montironi. I'm on behalf of Sebastian. Congrats on the progress. Thank you for taking my question. So I was wondering whether you could provide your thoughts or some insight on the recent approval of Blincyto in the consolidation phase of the multi-phase chemotherapy of the first line ALL. So, what do you anticipate the effect will be on the number of patients in the relapsed refractory setting of this disease? Thank you.

Christian Itin (CEO)

Thanks a lot for joining. A pleasure to have you along. So this is a question related to the recent approval of Blincyto in the frontline consolidation. Obviously, this is data that sort of has been, you know, first of all, known about for quite a while and presented over the last two to three years, both in consolidation of both MRD positive as well as patients, as well as patients that are gone through the initial induction and initial consolidation with chemo, high-dose chemotherapy, but then irrespective of status, got exposed to Blincyto. What's been very interesting about that part of the data is that when you look at the data a bit more carefully, you realize there's a subset of patients that appear to benefit.

There's another subset that does not appear to benefit from that consolidation. The group that did not appear to benefit actually were patients that were a bit older. That's a very interesting kind of observation. I think this is certainly something that I think we're, you know, need, needs some follow-up and I think better understanding. But it was clearly, you know, certain patients that did actually benefit, whereas others actually did not benefit at all. That's, you know, I think interesting, just when you look at that, at that part of it, at that part of the data. Overall, we think that most of the impact, actually, of the study has already been pretty much in the space.

Given that the data actually has been well known, it was an ECOG study, so there's a large number of centers involved. There's a lot of patients that actually will be managed and, in, in sort of, using Blincyto in the frontline setting. And in that sense, also is baked in. And you can see that also when you look at the trajectory of Blincyto sales, is that clearly the sales upswing actually went ahead of the approvals, although it was driven off exactly that data that was driving and actually ultimately was the, the basis for the approval. So we think most of that is actually baked in, and we do not expect to actually have a major impact on the relapsed refractory setting.

But certainly, you know, would expect that there is some delay of some of the patients actually becoming refractory, so buying some time. But we also believe that a lot of that actually already starts to be, you know, realized, and many of these patients actually start to get back to the point of relapse, given that, the consolidation has actually been used, for an extended period of time, certainly in the U.S.

Chiara Montironi (Biotech Equity Research Analyst)

Okay, thank you. Very helpful.

Christian Itin (CEO)

Thank you very much.

Operator (participant)

This concludes the question and answer session. I would now like to turn it back to Christian for closing remarks.

Christian Itin (CEO)

Well, thank you very much for joining. Really a pleasure to have you all on. I'm looking forward to keeping you updated, and, obviously, as we said, you know, all focus on getting to the final stretch and hopefully get to approval later in the year. And, be in a position where we can get this product to patients, which is really something that we've been working towards for many years now, and I think would be fantastic to be able to transition as we get to the end of the year to that stage. Thank you very much, and looking forward to keeping you updated.

Operator (participant)

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.