Autolus Therapeutics PLC (AUTL) 2021 Q1 法說會逐字稿

Hello, ladies and gentlemen, and welcome to the Autolus Therapeutics First Quarter 2021 Financial Results Conference Call. As a reminder, this conference call is being recorded. I would now like to turn the conference over to your host, Mr. Andrew Oakley, the company's Chief Financial Officer. Please go ahead.

Thank you, Rebecca, and good morning or good afternoon, everyone, and thank you for taking part in today's call on the financial results and operational highlights for the first quarter of 2021. I'm Andrew Oakley, the Chief Financial Officer; and with me today is Dr. Christian Itin, our Chief Executive Officer. Before we begin, I would like to remind you that during today's call, our discussion will contain forward-looking statements. All statements other than statements of historical facts on this call are forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the section titled Risk Factors in our annual report on Form 20-F filed with the Securities and Exchange Commission on March 4, 2021, which can be accessed on the EDGAR database at www.sec.gov, and in subsequent filings we make with the SEC from time to time. The forward-looking statements on this call reflect the company's views as of today, May 6, 2021, regarding future events and should not be relied upon as representing the speakers or the company's views as of any subsequent date. While the company may elect to update these forward-looking statements at some point, the company specifically disclaims any obligation to do so, even if the company's views change. These forward-looking statements should not be relied upon as representing the company's views as of any date subsequent to today. Please be advised that today's call is being recorded and webcast. On Slide 3, you will see the agenda for today, and it is as follows: Christian will provide a brief introduction, and that will be followed by our operational highlights for the first quarter of 2021. I will next discuss the company's financial results, and then Christian will conclude with upcoming milestones and other concluding comments. And of course, we will welcome your questions following our remarks. So with that, I'd like to now turn the call over to Christian. Christian?

Thank you, Andrew, and good morning to all of you, and thank you for joining us. I'm pleased to review our progress for the first quarter of 2021. First, and before we get to the update on our programs, we're very pleased to see the progress in the U.S., the U.K. and EU with the COVID vaccinations and seeing gradual decline of the case numbers. This bodes well for the conduct of our clinical trials as we move through 2021 and into 2022.With the expected opening of travel for vaccinated people between the U.S. and Europe, we also expect flight operations to start to gradually normalize, which will relax the pressure on logistics. We continue to work hard with our supply chain and logistics teams as well as our clinical centers to ensure timely continental and transatlantic deliveries of leukaphereseds final products and samples for analysis in order to support our clinical trials and ensure timely data availability and integrity. While we feel optimistic about the developments, we continue to monitor them very carefully with a particular focus on patient safety.In the fourth quarter last year, we provided data updates from the Phase I ALLCAR study at ASH. The FELIX study is progressing well and remains on track with data expected in 2022. In Q1, we have received the INN for AUTO1 and can now be referred to as obecabtagene autoleucel, or obe-cel.We also announced recently that we have received PRIME designation from the European Medicines Agency, again highlighting the innovative nature of obe-cel. We're also exploring the potential of obe-cel for the treatment of B cell non-Hodgkin's lymphoma, and we will have first data at EHA in June.Our next generation program, AUTO1/22, is being evaluated in pediatric patients with data expected for ASH at the end of this year. Phase I enrollment of AUTO4 continues. And importantly, we recently received an ILAP designation for AUTO4 from the U.K. Medicines and Health products Regulatory Agency, the MHRA, which may potentially accelerate regulatory review of the development candidate.Moving on to Slide #6 to discuss the corporate highlights for the quarter. In January and February, we strengthened our balance sheet with the sale of ADSs under our ATM facility for net proceeds of approximately $15 million and also a public offering of ADSs, raising approximately $107 million in net proceeds. In January, we highlighted our focus on the AUTO1 program and the conduct of the FELIX study. As part of this outlook, we announced our intention to partner our DLBCL program, AUTO3.We also reviewed our commercial manufacturing strategy and decided to build on our manufacturing setup in the U.K., being able to fully leverage our current manufacturing operations, experience and skill, resulting in a more economical manufacturing platform, while minimizing operational risk. In that process, we have terminated our lease of the U.S. manufacturing facility in Rockville.Moving on to Slide #7. We would like to remind you of the clinical profile of AUTO1 and how it compares to the standard of care. The primary treatment option for patients is blinatumomab, while inotuzumab may typically be used as a bridging therapy. If you look at the event-free survival, we also -- we are approximately twice as active as blinatumomab at 6 months and even at 12 months, we look -- we're at 52% for AUTO1 in terms of event-free survival, which substantially exceeds the 6 months value for blinatumomab at 31%. When looking at the AUTO1 data, it is important to realize that 70% of the patients had either received prior blinatumomab or inotuzumab and failed on those therapies before entering the AUTO1 trial.Despite the elevated AUTO1 activity compared to blinatumomab, cytokine release syndrome and neurotoxicity are very comparable. Put very simply, with AUTO1, we're looking at a program that has at least twice the level of clinical activity to blinatumomab, which is the current standard of care, with a comparable safety profile. We believe that data is very strong and an excellent foundation to move our product into the registrational study.Moving to Slide #8. Just another quick view on 2 of the key programs and products that are approved in the space, but from a commercial perspective. We're looking at BLINCYTO or blinatumomab and Besponsa or inotuzumab. As you can see, BLINCYTO reached, in 2020, annual sales of $379 million. Typically, patients received an average of 2 cycles of the product, which translates to approximately 2,100 patients treated with this commercial product globally. Note that the majority of patients, approximately 1,800, have received -- who received the product are adults.We understand the key driver for sales accelerating into the fourth quarter, which was 29% year-over-year, whilst the expansion to the community hospital segment in the U.S. beyond the academic transplant centers where the product was initially launched in. While BLINCYTO in ALL is moving to nonacademic centers, we also expect the launch of Breyanzi in DLBCL to establish CAR-T experience in those centers. Both developments bode well for a product with the properties of AUTO1.Let's now turn to Slide #9. First off, obviously, the AUTO1 program at this point is in motion in the FELIX Phase Ib/II pivotal study. It is a single-arm study with approximately 100 patients with relapsed/refractory disease. The primary endpoint is overall complete response rate. Secondary endpoints include molecular responses as well as event-free survival and duration of response. This program is ongoing and will recruit through the course of this year and into early next year.As I have mentioned, we're also conducting some additional studies to explore the activity of AUTO1 beyond the adult ALL population. That includes indolent lymphomas as well as other B cell non-Hodgkin's lymphomas and chronic lymphoblastic leukemia. As mentioned earlier, we're also exploring the activity in primary CNS lymphoma, which is typically a neglected indication.In December, we also started a next-generation version of the AUTO1 program called AUTO1/22 that looks at minimizing the relapse rate in pediatric ALL, driven by CD19 antigen loss. The AUTO1/22 program builds on AUTO1 with its unique properties and adds a novel highly active CD22 chimeric antigen receptor. We are planning to present data on this trial in the fourth quarter of this year.In summary, we believe there is a significant commercial opportunity to build on AUTO1 and a franchise around the AUTO1 program, anchored in ALL, both with adult and pediatric patients, and have an opportunity to expand further into the B cell non-Hodgkin's indications.Moving to Slide #10. AUTO4 is our T-cell lymphoma program currently active in the clinic, and we expect to have a clinical update by the end of this year and expect a good understanding by that point of the clinical profile of the product. The sister program, AUTO5, is prepared for an IND towards the end of '21. The medical need in T-cell lymphoma is high, with very limited available treatment options for patients once relapsed after frontline therapy.Moving to Slide 11. Always good to remind you all of the technology toolkit we have developed at Autolus, particularly as it relates to the suite of next-generation programs, some of which, you will recall, we showcased at AACR last year. We're looking to move several programs into the clinic through 2021 and into 2022, including our first solid tumor programs, which we're very excited to be progressing. Our cell program modules are designed to provide T cells with a high degree of specificity and activity against cancer cells, while strengthening the T cells' resilience to withstand hostile environment cancer cells create to fend off T cell attack.Slide #12. As you can see, we have tabulated here the next-generation programs alongside the expected Phase I start dates. I would like to briefly highlight 2 of our programs. You will note, as discussed, we started the pediatric ALL clinical trial for AUTO1/22 in December last year and are planning for a data update at the end of this year. We haven't yet mentioned, of course, AUTO6NG, which we expect to start a Phase I trial in children with neuroblastoma towards the end of 2021.This program builds on the positive clinical experience with AUTO6 published end of last year in Science Translational Medicine. All programs will initially be explored clinically in collaboration with our academic partners and will drive clinical news flow in 2022 and beyond.With that, I will turn over the call to Andrew for our first quarter 2021 financial update. Andrew?

Thanks, Christian. If we move to Slide 14, it's my pleasure to review our financial results for the first quarter of 2021.So starting with our cash position. Cash at March 31, 2021, totaled $239 million as compared to $153.3 million at December 31, 2020. In January of this year, the company sold 1.7 million ADSs under its open market sales agreement, resulting in net proceeds of $15.3 million. And in February '21, the company sold 16.4 million ADSs, representing 16.4 million ordinary shares, in a follow-on public offering including the exercise in full by the underwriters of their option to purchase an additional 2.1 million ADSs at a public offering price of $7 per ADS, yielding net proceeds of $106.9 million.Net total operating expenses for the 3 months ending March 31, 2021, were $39.9 million. That's net of grant income of $0.3 million, and that compares to net operating expenses of $38.6 million, net of grant income of $0.3 million for the same period in 2020. Research and development expenses decreased to $30.7 million for the 3 months ending March 31, 2021, from $31.3 million for the 3 months ended March 31, 2020.Cash costs, which exclude depreciation and amortization as well as share-based compensation, increased to $30.7 million from $25.6 million. This increase in research and development cash costs of $5.1 million consisted primarily of: one, an increase in compensation and employment-related costs, which is net of lower travel costs, of $3.5 million due to a combination of an increase in employee head count to support the advancement of our product candidates in clinical development and severance payments related to the reduction in workforce that began to take place during the quarter.Secondly, an increase of $2.2 million in facilities costs related to the continued scaling of manufacturing operations; and three, an increase of $0.4 million relating to cell logistics, which is offset by decreases in purchased materials in the amount of $0.6 million and project expenses of $0.4 million.Noncash R&D costs decreased to $36,000 for the 3 months ending March 31 from $5.7 million for the corresponding period last year. The decrease is primarily related to share-based compensation expense, which decreased by $6.2 million as a result of forfeitures of incentive share options related to employees affected by the reduction in workforce. And this was offset by an increase in depreciation of $0.5 million.General and administrative expenses increased to $8.7 million for the 3 months ending March 31, 2021, from $7.6 million for the corresponding period last year. Cash costs, which again exclude depreciation as well as share-based compensation, increased to $7.6 million from $5.9 million. This increase of $1.7 million is related to an increase, firstly, of $0.4 million in facilities costs; secondly, an increase of $0.6 million in legal fees and audit fees; and thirdly, an increase of $0.3 million of expenses related to preparations for becoming a commercial stage company; and lastly, an increase of $0.4 million in compensation and employment-related costs related to an increase in head count as well as severance payments related to the reduction in workforce that I mentioned earlier.Noncash general and administrative costs decreased to $1.1 million for the 3 months ending March 31, and that's from $1.7 million for the corresponding period last year. The decrease is attributed to share-based compensation expense as a result of the lower fair value of stock options recognized during the period. Loss on disposal of leasehold improvements of $0.7 million relates to resold improvements no longer being utilized in the facility in White City in London.Interest income decreased by $0.5 million for the 3 months ending March 31, 2021, due to lower interest rates for cash held on deposit. Other income decreased by $3.7 million for the 3 months. That compares to other income of $4.5 million in the corresponding period last year.There was a decrease of $5.6 million, primarily due to the weakening of the U.S. dollar relative to the pound during the 3 months ending March 31, 2021, and that compares to the 3 months ending March 31, 2020, which is offset by gains on lease terminations of $2 million. That's net of the related -- any related expenses.Income tax benefit increased to $5.7 million for the quarter, and that's up from $3.7 million for the corresponding period last year, and this is due to increased research and development credits. As research and development credits grew at a faster rate than our net loss before income tax, this led to a higher effective tax rate. Research and development credits are obtained at a maximum of 33.5% of our qualifying research and development expenses, and the increase in the net credit was primarily due to an increase in those eligible expenses.Net loss attributable to ordinary shareholders was $33.3 million for the 3 months ending March 31, 2021, and that compares to $29.9 million loss for the same period in 2020. The basic and diluted net loss per ordinary share for the 3 months ending March 31 was $0.53, and that compares to a basic and diluted net loss per ordinary share of $0.60 for the 3 months ending March 31, 2020. Our current cash on hand, which obviously includes the recent financings in January and February, will extend the cash -- the company's cash runway into the first half of 2023.And now with that, I will hand the call back to Christian to give you a brief outlook on expected milestones. Christian?

Thanks, Andrew, and let me conclude this part of the management discussion on Slide 16 with a recap of the major messages from today's call.The company is in a good position. And combined with our cash on hand, we feel well poised for success. We're very excited about the AUTO1 program. We continue to enroll into the FELIX study in adult patients with ALL and expect to report data in 2022.We started the Phase I program for the AUTO1/22 product in pediatric ALL patients at the end of last year and expect first data to read out in Q4 this year. Additionally, we expect first data from the ALLCAR extension program at EHA to give us first data on patients with non-Hodgkin's lymphoma. We're also planning to expand AUTO1 into primary CNS lymphoma with the CAROUSEL study, which is actually expected to start imminently.As indicated in our business outlook in January, this year, we have announced our renewed focus on the AUTO1 program, while intending to partner AUTO3 and 4 for the treatment of DLBCL patients. Additionally, we expect Phase I data from our AUTO4 program, our program for the treatment of patients with peripheral T-cell lymphoma, later in the year and expect multiple next-generation development candidates to enter clinical development over the course of 2021 and in 2022.Finally, with our successful recent raise, we are in a position of strength with a cash runway into the first half of 2023. We're now happy to take questions. Operator?

(Operator Instructions)

And your first question comes from the line of Mara Goldstein.

Great. I'm wondering if -- since we're expecting data on both the ALL programs starting in the fourth quarter of this year and then, obviously, the FELIX program in 2022, if you could maybe just sort of wrap some color around what we should be anticipating in terms of number of patients, duration of treatment?And then secondarily, on the AUTO8 program, you're going into a BCMA-directed CAR. And I'm just curious as to what your thoughts are from a competitive landscape perspective given the development in that space and whether or not AUTO8 may, to some degree, suffer the same fate as AUTO3 in terms of your prioritization and how you think about developing that?

Thanks, Mara. I appreciate the question. So first, with regards to the work we're doing in the ALLCAR study, to sort of explore the activities in the non-Hodgkin's indications as well as the CAROUSEL study for patients with primary CNS lymphoma. Those are exploratory studies. So we're basically having, as part of the ALLCAR extension, we're having a cohorts of approximately 10 patients each in each of the subindications, and that is what we're expecting to actually report on at the end of the year. So it gives us a -- overall, will give us a nice additional set of patients, and I think will give us a good feel for the performance of the product that we're seeing across those various indications.On the pediatric study, with the AUTO1/22 program, obviously, that's a classical Phase I study as well. And we expect the study to be enrolled by the end of this year and data available by -- for the -- for all of those patients. In terms of follow-up, obviously, the follow-up will be limited because most of these patients are being enrolled and treated during the course of this year. So we're looking at -- typically at a few months of follow-up for these patients on average.The third question or area that you were touching on is the AUTO8 program and the -- basically, the competitive environment in the multiple myeloma space. Now obviously, with the approval of obe-cel, but also the J&J program actually getting close to market as well.So what we're doing with this program -- and again, this is a program we're running first through an exploratory Phase I study on the academic side, is to actually evaluate whether indeed we can actually induce a high degree of deep responses in patients and whether we do see a good level of persistence to the product. Both I think we believe are characteristics that are important to actually provide a product that has an opportunity for a differentiated profile.You're absolutely correct in asking the question, what about the profile that we actually need to meet. And clearly, we do set a very high hurdle for a multiple myeloma program given where the standard of care is, not just from a CAR-T perspective, but overall, the standard of care, obviously, is -- has been moving quite significantly over the last few years, and we clearly would need to actually see a good probability of inducing true long-term remissions in these patients, which has still been a challenge to induce with, frankly, any modality at this point in time.

Okay. And if I could just ask, Andrew, can you remind us on the ATM program? What is left outstanding on that program?

Yes, Mara, I can. It's around $80 million.

Your next question comes from the line of Matt Phipps.

Christian, I guess, first, at EHA, which I think abstracts will be coming out next week, should we expect some data across all 3 cohorts from that ALLCAR trial? Or is it just mainly going to be indolent kind of updates beyond the 4 patients at ASH?

Thanks for joining, Matt. The update will be focused on the indolent cohort.

Okay. And then kind of following up on AUTO8. I guess the -- UCL posted the trial of a BCA (sic) [BCMA] CD19 dual CAR for BCMA -- for multiple myeloma and just wondering if you're at a point we can talk about the decision to use CD19 here versus maybe some of the newer targets like bispecifics have shown such as [TPRC5D].

So the way we're thinking about the AUTO8 program is that the program is anchored in -- with -- through the BCMA CAR. The CAR that we designed there actually has a very different -- quite a different binder to -- in terms of properties as well to what has been worked so far in the space and also uses a different actual design in terms of structural design that we're using for the receptor. So it's a significant change to certainly what we have initially in our AUTO2 product, but also what we're seeing across the current programs that are being moved forward. So that's the anchor basically. And what we're looking to get to is, as indicated, new set of responses, which is really the hurdle that the program needs to take first to be sort of be moved forward.The next layer of questions that I think you -- we need to address in the space is you actually get to a long level -- an extended level of persistence, which has been actually quite challenging in multiple myeloma. When you look at the current programs, the data that has been reported so far. So what we're looking to actually add is an element that actually gives us an extended persistence with the program.And the third area actually will be to address the quite heterogeneous as well as challenging microenvironment that we find in multiple myeloma. The reason why this is still a disease that is, basically, we can buy time, but we have a hard time to be getting to cure. So there's still remnants of tumors that we can't get to and there's situations that were clearly very challenging to sort of actually for an immunological, and frankly, any other approach to currently crack.So those are the 3 layers that we're basically working on. And so in terms of the target antigen that we're using, there is an importance there is to actually drive persistence, which is a key aspect of it and potentially actually support some of the driving cells that we see in multiple myeloma and be able to actually get at those, which may actually, in part, carry BCMA, but also maybe in part BCMA negative.

Okay. I mean, you kind of touched on this, but -- I mean, especially, with the J&J product, I mean the CR rates are extremely high. Do you think you can meaningfully...

Correct.

I guess, is there an ability to meaningfully beat that as opposed to just -- the real thing here is to drive better persistence to get that improved PFS beyond -- meaningfully beyond the year for PFS?

You're right in pointing out that, obviously, the CR rate percent is very high. But I think the more interesting part of the data is that the depth of the CR rate actually is correlated with the length of outcome. And what you need to drive towards are very deep responses with very stringent molecular CRs. And that is actually where you start to see differences, also differences between obe-cel and the J&J program. And that is the area that you really need to actually drive at.So it's actually to look at a very high level of stringency with regards to the molecular CRs that you're actually looking at, then that gives you an early readout. And then you're right, the next level is very clearly that you need to actually drive for persistence and have ability to actually keep the product active over an extended period of time.And the third aspect, as we're seeing with -- in the space, it's certainly also related to the overall safety profile that we're seeing as well.

And kind of last, broader question. Given kind of what we've seen with AUTO1 on the level of expansion and persistence and safety, do you keep that in mind as far as using a lentiviral system with this construct and just maybe with different scFv in programs going forward? Or how you manage kind of the different backbone, so to speak, of the programs?

I think in indications where persistence is important to sort of actually get to long-term benefits, we clearly do see a benefit of using the lentiviral backbones. And that's obviously what we're using in the context of the -- obviously, leukemia as well as multiple myeloma, you'll be -- you'll also be looking at a lentiviral backbone.

Your next question comes from the line of Gil Blum.

So with the focus of manufacturing in the U.K., could this offer some logistical issues in treating patients in the U.S.?

Well, thanks a lot for joining, Gil. Very good question. Obviously, we're -- we actually manufacture for our clinical trials currently out of the U.K. -- out of the manufacturing site that's located north of London in Stevenage. And we've been able to actually serve all the various geographies within the U.S., obviously, as well as across Europe within the time frame required to actually shift, not only frozen leukaphereseds, but also fresh leukaphereseds.So we can actually manage the logistics very well even -- and we're able to do that even during the most limited flight patterns that we have during the course of last year. So we don't think that actually that adds a significant component here in terms of either time or risk from a logistics perspective.

Okay. And maybe a little bit about AUTO6NG here. So neuroblastoma in children is a relatively small market. Could you kind of remind us what the specialized features of AUTO6NG and how those might translate across your solid tumor platform and learnings that you could have from a study in relatively small indication?

Right. So the AUTO6 program, AUTO6, started out with a chimeric antigen receptor targeting GD2 and was first asking the question, can we actually generate an adequate therapeutic window targeting GD2, understanding that there is a low amount of GD2 also present in pain fibers. And that basically -- that question was answered through the first trial and was the publication that we had at the end of last year in Science Translational Medicine.The next question, however, is then, once you have an ability to target is to actually address the challenges that are derived from the microenvironment that is present in neuroblastoma, and frankly, for that matter, in most solid tumors. What we're doing with the program is actually building quite significant level of resilience into the cells, into the CAR-T cells. And we do that in 3 different ways.On the one hand, we're actually rendering the cells insensitive to checkpoints or checkpoint signals by using an intracellularly available dominant negative version of SHP2, which is a protein that transmits normally the signal from a checkpoint onto a T cell receptor, like chimeric antigen receptor. The dominant version of it -- of SHP2 actually abolishes that signal transduction. And with that, basically renders the cells insensitive to that negatively -- to that negative set of signals coming from checkpoint receptors.The second element is TGFBeta, which is certainly one of the ways and have tumor cell actually defend and fend off T cells and other immune cells over a distance. Here, we're rendering the cells insensitive to actually transmit the TGFBeta-induced signal into the interior of the CAR-T cell and be using, again, a dominant negative version of a receptor subchain that is part of the TGFBeta receptor.And the third element that we're adding is constitutively active IL-7 signal, actually using a receptor that sort of actually gives you an IL-7-like signal on a competitive basis. And what that does is actually, it actually helps the CAR-T cells to keep activated and actually even if they receive negative signals from the environment, keep overcoming those. IL-7, just as a reference, is also what we're inducing when we actually do the conditioning regimen on the chemo stretch upfront any of the CAR T therapies, it's actually to induce IL-7 and IL-15.And obviously, with the very same reason to actually help the CAR-T cells actually take hold at that point. And always in the case of actually having this signal engineered into the cells to actually keep them going, even if the environment actually is difficult to manage. Now these 3 components I just talked through, obviously, are components that are relevant for any program, we believe, in the solid tumor setting. And hence, actually, the data that we're going to be generating in neuroblastoma will be important, not just for neuroblastoma, but across our various programs also that we've been working on towards other tumor entities as well.So I think that is sort of the important part. The reason why we're actually exploring these modules in neuroblastoma first is because in neuroblastoma, we have a homogeneously expressed target antigen, in the case of GD2, which actually takes one of the elements of variability out that you often have with tumor-associated antigens, which often are highly variable in their expression, think about HER2 or EGFR, as an example, which are -- have a wide range of expression across cells within a given tumor sample.And that obviously creates a lot of challenges, in fact, if you try to interpret results, you actually generate. So here we have a homogeneous background. It's a high medical need setting. It's a pediatric indications. It's obviously a very good fit with the pediatric work we're doing in ALL from a center perspective, from a commercial perspective as well. But it also gives us a very good background and clean background to actually establish those additional modules and their utility in a solid tumor setting.

That was very helpful. And last one on the indolent lymphoma program. Could you remind us how important is having a safer lower CRS CAR-T product in this patient population, maybe with a look at competitive programs here?

Thanks, Gil. This is a very important question because, obviously, when we look at the CAR-T experience so far that we have through the initial programs that reached commercial stage, is that we -- although we expected the CAR-Ts to go very broad in a lot of their indications, DLBCL first, but then also now with approvals in follicular mantle cell, that we should be able to reach a large proportion of patients and the reality is we haven't been able to do that.The fundamental reason why that didn't happen is that actually managing the CAR-T therapy in centers outside of highly specialized transplant centers has been really difficult. And it's difficult from a handling perspective, from an infrastructure perspective, from a cost perspective. And so the adverse event profile and, in fact, hematological adverse event profiles of the product, actually has significantly limited their commercial use and, frankly, have limited their ability to actually reach the majority of the patients in those disease settings.Now if you go into a disease setting like follicular lymphoma or also mantle cell lymphoma, or CLL, for that matter, is that those patients very often are treated much more into the periphery, even more so than what we're seeing in DLBCL as an example. And that actually creates a very significant need for an excellent safety profile so that, indeed, the therapy can be managed outside of the highly specialized academic centers. And that's really what is the core and what is needed in terms of the commercial translation of this therapeutic approach, to reach a broader range of patients in their respective indications.

Your next question comes from the line of Eric Joseph.

This is Rahul on for Eric. Just a couple from us. Firstly, on AUTO1, how do you assess its potential in the earlier line settings in adult ALL? I mean what kind of response and durability would be seen as clinically meaningful relative to the existing treatment landscape? And then is it safe to say that the initial approval would likely be in the third-line setting followed by a potential label expansion based on the confirmatory Phase III study?

So thanks a lot for joining and thanks for the questions. Obviously, where we're starting with the development for AUTO1 in ALL is the last line setting. The challenge at that point that the patients have is that they've already experienced an enormous amount of cytotoxic agents. And as a consequence of that, are both highly immunosuppressed, but also are overall in a rather poor condition because of the high level of cumulative toxicity they've been exposed to.So in that sense, it's actually a very difficult population to deal with, both from a safety perspective, but also from a disease perspective, because, obviously, with every line of therapy, you keep selecting the cells that withstand, obviously, that particular line breakthrough. And actually, at that point, obviously, are more difficult to treat. And so starting at the last line setting and actually showing a significant level of activity in this last line setting bodes extremely well in terms of the potential of the product in an earlier line.This was also exemplified very nicely by the experience in adult ALL patients with blinatumomab or BLINCYTO, where the last line or third line data was showing a complete remission rate of approximately 42%. However, in frontline consolidation, in patients who actually have gone through front line induction chemotherapy constellation cycle one, and at that point, still have minimal residual disease, which was obviously resistant to chemo. In that patient population, BLINCYTO actually showed 78% complete remission rate.So in other words, what we're seeing is that as you move up, and this is obviously also T cell-mediated activity. As you move up, we would expect actually that the activity we're seeing and the benefit that we're seeing induced in the third-line patients to substantially improve as we go into an early line of therapy. And that is what we would expect to see.And clearly, in terms of the settings that you can think about is similar to what I just said with regards to front line consolidation of high-risk patients is one setting you might want to go or you could also contemplate a more classical second-line setting, either in patients that are ineligible for transplant or patients that are eligible for transplant. Those are the basic settings that you can choose to actually move the product into an earlier line of ALL therapy.

And then on AUTO3, can you maybe clarify the Phase I, II ALEXANDER studies as a store for additional data readouts and news flow in 2021, such as survival follow-up and safety data from the outpatient cohort?

Right. So on the AUTO3 program, we're in the process actually of writing up the data in a publication. Given that we obviously had 4 oral presentations of the data last year, we feel it's the right time to actually now show the full picture of the data, which is only possible in a limited way in 10-minute presentations and hence, we're moving to a publication, which we're hoping to publish during the course of this year.

Your next question comes from the line of Kelly Shi.

I have a question regarding AUTO4 in T-cell lymphoma. So what kind of patients do you enroll on this trial? And what does the competitive landscape look like? Also for the ASH update at this year-end, should we expect to see meaningful efficacy readout?

Thanks a lot, Kelly, for joining. So the patients who are enrolling in the AUTO4 Phase I trial are patients with peripheral T-cell lymphoma that have failed, obviously, not just the front line therapy, but typically, 3 lines of therapy before they actually get on to our trial. So these are very advanced patients that we're enrolling into the trial. The -- what we're expecting to see towards the end of the year is, obviously, we're going through the dose escalation with the program, and we expect data from currently what -- would assume data from 3 dose levels at that point in time, potentially a bit more than that. But that's sort of the ballpark that we're looking at.So we're looking at the dose escalation and, obviously, the readout related to that. In terms of the data that we expect to see is, obviously, safety data as well as all of the tumor assessments in those patients and pharmacological pharmacodynamic type of data, which should give us a good understanding of the performance of the product in that setting.From a competitive perspective, at this point, I would say the competitive environment in PTCL, late-stage setting, is rather limited. There's obviously the subset of patients that are CD30 positive, which are eligible for rituximab, which is unfortunately only a small portion of the patient population. For the patients that are not eligible for rituximab, obviously, the current opportunity is predominantly actually to participate in clinical trials.So in that sense, there is not a -- from a commercial perspective or a therapy perspective on the market, there is a very small sort of set of agents that are currently available, predominantly related to high-dose chemotherapy, potential transplant and if you're CD30 positive, rituximab.

I also have a follow-up for AUTO6. I'm just wondering, so for the safety switch incorporated in the CAR, at what juncture would physicians be allowed to trigger the safety switch?

So when we designed the original AUTO6 program, obviously, the question that we had was really the question around the safety of the product and whether indeed we could get actually to clinical activity without inducing significant neurological toxicity, in this case, a very major pain syndrome. And -- because we couldn't predict whether or not our hypothesis around design actually would be working out. Obviously, we did put an off switch into the product, which would allow the product to be eliminated should that become a necessity.With the product actually having gone through the initial exploration in Phase I in neuroblastoma patients and without actually inducing that type of toxicity, I would expect that it's quite unlikely that a physician would actually want to use the switch. And certainly, we didn't have a need to use it.I think, in general, when you actually offer switches built them into your product, it's really the physician's decision and it's the physician's call in the end whether or not to actually, frankly, abort the therapy, which is what it is. In this case, you would be providing a dose of rituximab, which would take out the CAR-T cells, at which point you literally abort the therapy.So you do that clearly if you have indication of a significant level of toxicity that you have a hard time controlling. And -- but this is ultimately the decision of the treating physician that -- where that -- frankly, that decision has to reside.

Your next question comes from the line of Asthika Goonewardene.

I got a couple on AUTO8, if I may. Can you -- Christian, can you talk about the design features of the CAR that could help you get more of those stringent CRs or more patients into MRD negativity? And then what items in your toolkit are you incorporating that could help AUTO8 overcome some of the suppressive factors in the tumor microenvironment? And then I have a follow-up on AUTO1.

Okay. Well, thanks, Asthika, for joining. What we really were working towards and what the design work that we've done on the receptors actually was geared to, is to get to a very high level of cytotoxic activity of the product against multiple myeloma cells that express very low amounts of BCMA. What we had published earlier is that the range of BCMA expression can vary quite a bit in these patients.It can be as low as 10, 20 receptors per cell. Up to -- in the low thousands of receptors per cell. But in general, it's an order of magnitude -- 2 orders of magnitude below what is an example of CD19 would be. So the real challenge is how do you get to these cells that actually express very low amounts and to sort of be -- still be very active on those [myeloma] cells.And that is really the test that we applied, and we did actually test a range of different types of binders as well as designs on the receptor that -- for exactly that ability to give us a very high level of activity against those multiple myeloma cells that express very, very low levels of BCMA, and it still has to work there. That's really the optimization that really was driving the selection for those features on design, et cetera, that will give you exactly that outcome. So it was a series of designs tested for a particular outcome, and that is actually how that -- how we sort of actually addressed the fundamental question that we believe is at the heart of the improvement that needs to be done.With regards to the toolkit, I think what I just went through with regards to the key elements that we're using as an example for the AUTO6NG program, actually, those elements, all we believe, would be relevant as well in the context of multiple myeloma. The exact composition we haven't disclosed at this point. But I think any of these modules actually would be, we believe, supportive in terms of activity and drive further activity in that setting.

Great, Christian. And then -- so just going to AUTO1 here. So there's data that suggests that the upfront response may be a driver of durable -- or maybe a driver of durability in DLBCL. Do you think there's data in the public domain that suggests that this also is the case with indolent lymphoma? Or is persistence something that's more important in this setting? Kind of to put the question in another way, I'm trying to figure out how does AUTO1 do better than, let's say, Acticell, which also has generated some data in [indolent lymphoma]?

Right. So it is an interesting question, actually, in terms of depth of response. I think the best data and also correlative data with outcome that we have across the B-cell malignancies is actually in ALL, where we have excellent data sets that actually show the impact of molecular responses and the importance of reaching molecular responses to outcomes, whether you're looking at patients who do receive subsequent transplant or whether you look at in the context, obviously, of other therapeutic modality. But getting to a molecular response is critical for a chance to actually have a long-term outcome. If you don't achieve that, your disease will come back very, very quickly.The data set that we're seeing in multiple myeloma starts to point quite similar way, as we talked about before. And I think it sort of gives us a very similar picture. I think that we're starting to gain more information around non-Hodgkin's lymphoma more broadly. But the data sets are probably not quite as strong yet in terms of the correlation between the molecular remission as well as the long-term outcome, it's just data that is still actually being generated. But in general, I think there is a sense that getting to very deep responses matters, obviously, in a significant way in these disease settings.The -- With regards to follicular lymphoma, I don't think there is enough data to use it as a guide quite yet. But I think as we're looking into the next 2 or 3 years, I would expect the field will start generating much more substantive data sets that will give much more conclusive answers around the correlation of molecular remissions and durability of response in those settings as well.

Your next question comes from the line of Robert Burns.

This is Jake for Rob. My first question is on AUTO8. So thanks for the color on the optimized design. And do you think that would potentially help in eliciting lower CRs than neutropenia than something like J&J's asset, which showed pretty high rates in its Phase I study? And do you think the field has evolved to manage some of these toxicities? In other words, are these a major barrier to adoption?And a quick question on AUTO1 allogeneic program. Can you provide like an update on when you're potentially going to initiate a study and type of patients and maybe even the target?

Thanks a lot for joining, Jake. The question related to sort of multiple myeloma and the type of safety signals that we're seeing, I think that what we're obviously having multiple myeloma is a disease that actually is present -- similar to ALL, it's present in the bone marrow. And it has significant impact on sort of the health of the bone marrow of the patients. And that obviously can drive -- ultimately has an impact on cytopenias, et cetera, and prolonged cytopenias, of course, as well.So I think it is -- we have an element here that's intrinsic to the disease. We've been obviously working with therapeutic approaches that actually are highly active and have to be highly active in the marrow, and can drive significant levels of cytokines in these patients in the marrow as well, which can have actually a negative impact on the bone marrow's ability to regenerate.I think what we'll have to see and we'll probably need a bit more data on that, though, in general, in the field is, at this point, does the marrow actually start to recuperate and sort of actually start to compensate -- basically rebuild its ability to properly function. It is -- that is something I think that we just need more data on. And I'm not sure there's a good lead at this point that will give you a sense around design premises, et cetera, that you need to actually look at to improve the outcome with regards to these types of toxicities.Second question that you raised was related to the activity that we're doing -- having on the allogeneic side, that the program that you're referring to is also one, obviously, that is in collaboration with our academic partners. And we expect that program to actually get going towards the middle of the year, and we'll report at that point in time and give an update kind of on where we're going with the program. So it will still be a bit of time here to actually -- before we're going to start to talk about it in more detail. But that program is obviously on track to be initiated during the course of this year and on the clinical side.

At this time, there are no further questions. Do you have any closing remarks?

Well, first off, thanks a lot for joining. Really appreciate your continued interest and support, and we're looking forward to keeping you updated. Obviously, next key update for us will be at EHA. All right. Thank you very much. Have a great day.

Thank you for participating. This concludes today's conference call. You may now disconnect.