Autolus Therapeutics PLC (AUTL) 2020 Q4 法說會逐字稿

Hello, ladies and gentlemen, and welcome to the Autolus Therapeutics Fourth Quarter 2020 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, Dr. Lucinda Crabtree, Vice President, Investor Relations. Please go ahead.

Thank you. 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 fourth quarter 2020. I am Lucinda Crabtree, Vice President of Investor Relations. With me today are Dr. Christian Itin, our Chairman and Chief Executive Officer; and Andrew Oakley, our Chief Financial 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 3, 2020, 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, March 4, 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 future 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 fourth quarter of 2020. Andrew 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.

Thank you, Lucinda, and good morning to all of you, and thank you for joining us. I'm pleased to review our progress for the fourth quarter 2020.

First, on Slide 5, I would like to provide an update on our programs. We have now entered into a more stable period post the initial COVID peaks last year, and our programs remain on track. We have not seen any further disruption in the fourth quarter last year. 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 leukapheresates, final products and samples for analysis.

In order to support our clinical trials and ensure timely data availability and integrity, we continue to monitor developments very carefully with a particular focus on patient safety. In Q4 and indeed, the full year, we provided data updates from our Phase I ALLCAR study of AUTO1 at EHA in June and also at ASH in December 2020. The pivotal program, AUTO1-AL1, which we now can also refer to as the FELIX study, remains on track with data expected in 2022. We also provided an update from the ALEXANDER study of AUTO3 in DLBCL at EHA and also at ASH last year. I will touch on AUTO3 a little later.

In addition, our academic partners published data from a Phase I study of AUTO6 in the journal, Science Translational Medicine, and we're looking forward to moving AUTO6NG into clinical development. In January this year, we provided a business outlook where we guided on a renewed focus on the AUTO1 program. As part of this outlook, we announced our intention to partner our DLBCL program, AUTO3.

Finally, in January and February '21, 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 $108 million in net proceeds. More detailed updates will follow on the next slides. So moving on to Slide 6.

We're focusing our AUTO1 program on addressing the high unmet medical need in adult acute lymphoblastic leukemia, which is a truly underserved area with limited treatment options in development. The FELIX study is designed to address the relapsed/refractory population, with data expected next year building on the unique profile of AUTO1. We're also exploring its [safety] in relapsed/refractory, BNHL indications and in primary CNS lymphoma.

In addition, the next-generation program, AUTO1/22 is being explored in pediatric patients. We expect data updates for these programs in the fourth quarter 2021. Beyond data in B-cell malignancies, we expect clinical data from AUTO4 in peripheral T-cell lymphoma in the fourth quarter and are moving our next-generation programs forward into clinical development in collaboration with our academic partners.

Moving to Slide 7. Focusing on our lead program in adult ALL, I think it's important to understand that with this indication, we have no approved CAR-T therapy at this point in time. The only approved redirected T cell therapy is Blincyto or blinatumomab. And in terms of other targeted therapies, there is also inotuzumab, a CD22 targeting antibody drug conjugate.

Frontline therapy is very intense based on -- very intense high-dose chemotherapy regimens. Most patients do respond to that initial therapy. The challenge, however, is that only 30% to 40% of the patients benefit long term, while the majority of those patients relapse. Once relapsed, life expectancy is very short, with a median survival of less than 1 year.

The relapsed patients, when they're fit enough, will receive a high-dose chemotherapy, followed by an allogeneic stem cell transplant with a small proportion of patients achieving a long-term benefit. Patients not eligible for stem cell transplant or relapsing post transplant may receive additional chemotherapy, blinatumomab or inotuzumab. However, none of these therapies drive long-term benefit at that stage of the disease. This is a very challenging situation for patients and their treating physicians.

At this stage, these patients are typically in quite poor condition, both from the immunosuppressive nature of their underlying disease and as a consequence of the often multiple courses of high-dose, very toxic chemotherapy. As a consequence, a lot of these patients are highly prone to infection and a lot of them do die of sepsis as the primary cause of death.

The core of relapsed/refractory adult patients in the U.S., EU and Japan are approximately 3,000 patients with high unmet medical need and very limited new therapeutic options in development.

Turning to Slide #8. We've pulled together a funnel to illustrate the treatment journey for patients diagnosed with adult ALL. Unlike pediatric ALL, high relapse rates are common in adult ALL despite favorable initial responses and, therefore, opening the door for a product like AUTO1. The significant unmet need in relapsed/refractory adult ALL necessitates new innovation, which can offer improved durability, safety and curative intent.

We will initially look to target those patients post receiving blina or inotuzumab, but also expect to capture some patients prior to having been exposed to these standard of care agents. The initial indication represents approximately 3,000 patients, and we expect data in the last line setting will drive interest to move the program into earlier lines of therapy.

On the next slide, #9, we summarize the key features of a successful CAR-T cell therapy for adult ALL. The basic disease challenges involve very fast proliferating leukemic cells with almost stem cell-like proliferative potential in patients who are in overall poor condition as a consequence of their underlying disease and also the toxicity of prior treatments. So the product needs to combine very high levels of sustained and leukemic activity with a good tolerability profile.

The technical solution for CAR-T -- for the CAR-T product, AUTO1, is its highly specific but transient engagement of the leukemic cells, maximizing its activity and persistence while minimizing cytokine release of neurotoxicity. The result is a high molecular response rate and event-free survival, combined with a manageable safety profile.

Moving to Slide 10. We would like to highlight some of the key data presented in December at ASH. The event-free survival at 6 months was 69% and at 12 months, 52%. Overall, we showed a median follow-up of the patients of 16.9 months and first patients without receiving a second transplant passed 24 months in sustained molecular complete remission with persistent CAR-T cells. This profile gives us a lot of hope that the program can drive long-term remissions in a proportion of patients. We're now conducting the FELIX study to confirm these results.

On the next slide, #11, we are looking to put the AUTO1 data in the perspective of 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're approximately twice as active as blinatumomab at 6 months. And even at 12 months, where we are seeing a value of 52% event-free survival for AUTO1, we see a substantial exceeding data compared to the 6 months value for blinatumomab of just 31%.

When looking at the AUTO1 data, it is important to realize that 70% of the patients had either received prior blinatumomab or prior 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.

In a very simple way put, with AUTO1, we're looking at a program that has at least twice the level of clinical activity of blinatumomab, which is the current standard of care, with a comparable safety profile. We believe that the data is a very good foundation to move this product into a potential registrational study.

Moving to Slide 12. 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 has reached in 2020 annual sales of $379 million. Typically, patients receive 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 receiving the product are adults. We understand the key driver for sales accelerating into the fourth quarter was the expansion to community hospitals and segment in the U.S. beyond the initial academic transplant centers, which were where the product started its journey.

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 13. First off, obviously, the AUTO1 program at this point is in motion with 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.

As I've mentioned, we're also conducting some clinical additional studies to explore the activity of AUTO1 therapy for the adult ALL population. That includes indolent lymphomas and CLL. 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 that looks at minimizing the relapse rate in pediatric ALL, driven by CD19 antigen loss. The program is called AUTO1/22 and builds on AUTO1 with its unique properties and add a novel highly active CD22 chimeric antigen receptor. Data presentation is planned for Q4 in 2021.

In summary, we believe there's a significant commercial opportunity to build an AUTO1 franchise anchored in ALL, both with adult and pediatric patients and also expanding into additional B cell non-Hodgkin's lymphoma indications.

Turning to Slide 14. Moving to our next program, AUTO3 in diffuse large B-cell lymphoma. We've provided updates and oral presentations of the ALEXANDER study at ASCO, EHA, ESMO and ASH last year. The program has shown a high level of clinical activity, paired with a very favorable safety profile.

Two regimens of pembrolizumab were tested and shown to be safe. And building on what we believe is a best-in-class safety profile, we tested AUTO3 in outpatient setting and demonstrated feasibility. Of the patients administered in the outpatient setting, 38% were admitted with fever due to concerns of potential infection and all were discharged after the risk was cleared. Patients were all -- were well managed, manageable without need for intensive care. We're planning to partner the program, considering the broad commercial footprint required to serve the outpatient setting.

So let us turn to Slide 15. AUTO4 is our T cell lymphoma program currently active in the clinic, and we expect to have a clinical update at the end of the year and expect a good understanding of the clinical profile of this product by then. The sister program, AUTO5, is prepared for an IND towards the end of 2021. The medical need in T-cell lymphoma is high, with very limited available treatment options for patients once they relapse after frontline therapy.

Moving to Slide 16. Always to remind you all of the technology toolkit we've developed at Autolus, particularly as it relates to the suite of next-generation programs, some of which, you will recall, we showcased at AACR in 2020. We're looking to move several programs into the clinic through 2021 and into 2022, including our first solid tumor programs, which we are very excited to be progressing.

Our cell programming modules are designed to provide T cells with a high degree of specificity and activity against cancer cells while strengthening the T cell's resilience to withstand the hostile environment cancer cells create to fend off T cell attack.

Slide 17, you can see we have tabulated these next-gen programs alongside the expected Phase I start dates. As you will note, and as discussed, we started the pediatric ALL clinical trial of AUTO1/22 in Q4 last year. We haven't yet mentioned, of course, AUTO6NG, which we expect to move into a study of CD2 positive solid tumors, and particularly in neuroblastoma, second half of this year. AUTO7 in prostate cancer is due to enter the clinic next year. And finally, AUTO8 will move into the clinic in the first half of '21 in multiple myeloma. All programs will initially be explored clinically in collaboration with our academic partners.

Now with that, I would like to turn to Slide 18 to tell you about a project we incubated with our research team in 2020. This is a program we will look to actively partner in 2021. As we started to learn about the SARS-CoV2 virus in Q1 last year, we got concerned about 2 areas that did not feature at the time in many of the discussions on the virus. The first was the risk of mutational drift, which was known for coronaviruses in general, but at the time, not well-established for SARS-CoV2; and the second were the challenges this viral infection could pose for our patients with B cell malignancies with multiple myeloma, who would likely only have limited ability to benefit from future vaccines.

We considered that vaccine approaches as well as antibody-based therapeutic approaches may not work well for our patients, and more generally, could be outsmarted by the virus. The approach we wanted to focus on should remain active, even if the virus were to undergo mutational drift and could be used as a universal decoy against not only SARS-CoV2 and its variants, but ideally against all coronaviruses using the same human receptors to infect cells.

What we developed is an ACE2 Fx fusion molecule, combining an enzymatically inactive form of the extracellular domain of ACE2 and a mutated constant domain from an IgG to avoid unwanted immune activation. This molecule can efficiently neutralize the virus by acting as a receptor decoy for the spike protein SARS-CoV2. The FC domain has been introduced to confer an extended half life to the molecule and improve effectiveness of the product.

The product candidate has been tested in vitro and in vivo against SARS-CoV2. We have now demonstrated in, in-vitro models, the efficacy of this product candidate against the U.K. B117 and the South African B1351 variance, using lentiviral vector pseudo type to address the SARS-CoV2 spike protein.

In addition, we also tested the ability of the product to neutralize SARS-CoV1 to further highlight the potential utility against a wider range of ACE2 tropic viruses. As you can see, only the ACE2 Fx neutralizes all SARS-CoV2 variants, whereas therapeutic antibodies lose activity against SARS-CoV2 variants and are inactive against SARS-CoV1, whereas, obviously, the product candidate is active against SARS-CoV1.

We're very encouraged by this early data and the opportunity to develop a potentially universally neutralizing agent against SARS-CoV2. As indicated, we're looking to partner the program for clinical development.

With that, I will turn over the call to Andrew for our fourth quarter 2020 financial update. Andrew?

Thanks, Christian, and good morning or good afternoon to everyone. So if we move to Slide 20, it's my pleasure to review our financial results for the fourth quarter to December 31, 2020.

So let's start with the cash position. Cash and cash equivalents at December 31, 2020, totaled $153.3 million as compared to $210.6 million at 31st of December 2019. 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 of this year, the company conducted a public offering of 16.4 million ADSs, including the exercise in full by the underwriters of their option to purchase an additional 2.1 million ADSs at an offering price of $7 per ADS, resulting in net proceeds of $108.1 million.

Net total operating expenses for the 12 months ending 31st of December 2020, were $168.1 million, net of grant income and license revenues of $1.7 million, and this compares to net operating expenses of $146.1 million, net of grant income of $2.9 million for the same period in 2019.

Research and development expenses increased to $134.9 million for the year ending 31st of December 2020, from $105.4 million for the year ending December 31, 2019. Our cash costs, which exclude depreciation and amortization as well as share-based compensation, increased to $116.9 million from $83.4 million. The increase in research and development cash costs of $33.5 million consisted primarily of -- firstly, an increase of $8.8 million in compensation and employment-related costs, that's net of lower travel costs due to an increase in employee headcount to support the advancement of our product candidates in clinical development. The lower travel costs, obviously, due to the COVID-19 pandemic.

Secondly, an increase of $14.4 million in project expenses as a consequence of the advancement of our clinical portfolio, which -- this includes research and process development and manufacturing activities necessary to repair, activate and monitor clinical trial programs.

Thirdly, an increase of $6 million in facilities costs, and that relates to the commencement of the lease for additional manufacturing suite and the continued scaling of our manufacturing operations. Fourthly, an increase of $4 million in IT infrastructure and support for information systems related to the conduct of clinical trials and manufacturing operations.

Fifthly, an increase of $0.5 million, related to professional fees. And lastly, an increase of $1.7 million related to cell logistics. This is all offset by a reduction in materials purchases of $0.7 million and license fees of $1.1 million.

Noncash R&D costs decreased to $18.1 million for the year ending December 31, 2020, from $22 million for the year ending 31st of December 2019. The $3.9 million decrease is related to a decrease of $4.8 million in share-based compensation expense as a result of a lower fair value of stock options recognized in the period, and that's offset by a $0.9 million increase in depreciation charges.

General and administrative expenses decreased to $35.0 million for the year ending 31 December 2020, from $39.5 million for the year ending December 31, 2019. Cash costs, which exclude depreciation as well as share-based compensation, increased to $27.4 million from $26.6 million. There were increases of $1.3 million related to D&O insurance costs and intellectual property and a $0.1 million in facility costs, and this was offset by decreases of $0.5 million in compensation and other employment-related costs and $0.1 million in general office expenses.

Noncash G&A costs decreased to $7.6 million for the year ending December 31, 2020, from $12.9 million for the corresponding period last year. The decrease of $5.3 million is mainly also again attributed to lower share-based compensation expenses as a result of lower fair value of the share options recognized during the period.

Interest income decreased to $0.5 million for the year ending December 31, 2020, from $2.5 million from last year. This decrease is due to lower cash balances held during the year and combined with lower interest rates for cash held on deposit. Other income decreased to $1.4 million for the year, December 31, 2020, from $4.5 million from the prior year, and that was primarily due to a weakening of the U.S. dollar exchange rate relative to pound sterling. The decrease of $4.6 million in the year ending December 31, 2020, was offset by lease termination gains of $1.5 million.

Income tax benefit increased to $24.2 million for the year ending December 31, 2020, and that compares to the $15.2 million for the year -- for the prior year, and that's due to additional U.K. research and development tax credits receivable from HMRC. Research and development credits are obtained at a maximum rate of 33.35% of our qualifying research and development expenses, and the increase in the net credit was primarily due -- attributable to an increase in eligible R&D expenses.

The net loss attributable to ordinary shareholders was $142.1 million for the 12 months ending December 31, and that compares to a loss of $123.8 million for the same period in 2019. The basic and diluted net loss per ordinary share for the 12 months ending December 31, 2020, was a loss of $2.76 per share, and that compares to a basic and diluted net loss per ordinary share of $2.88 for the 12 months ending December 31, 2019. We can now update that our current cash on hand, which includes the recent financings in January and February of this year, will extend the company's runway into the first half of 2023.

And with that, I will now hand the call back to Christian to give you a brief outlook on expected milestones. Christian?

Thanks, Andrew. Let me conclude this -- the management discussion with a review of the upcoming milestones and news flow through 2021. Let's move to Slide 22.

As we look at the year 2021, there are a number of clinical milestones and opportunities for value creation. Our chief and most imminent operational focus will be continuing enrollment and dosing of patients in the pivotal Phase Ib/II FELIX trial for AUTO1 in adult patients with relapsed/refractory ALL.

In addition, we have clinical activities or are planning to initiate clinical activities with AUTO1/22, AUTO4, AUTO6NG, AUTO8 during 2021 and are preparing AUTO5 and AUTO7 for clinical trials as well.

In conclusion, on Slide 23, I'd like to recap 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 patients and expect to report data in 2022.

We started the Phase I program with AUTO1/22 in pediatric ALL at the end of last year and expect first data to read out in Q4 this year. Additionally, we expect data at EHA in June from our ALLCAR study extension in indolent non-Hodgkin's lymphoma. We also are planning on expanding AUTO1 primary CNS lymphoma with the CAR cell study planned to start imminently.

As indicated in our business outlook in January this year, we have announced our renewed focus on the AUTO1 program. We're intending to partner our lead program, AUTO3, before progressing it into the next stage of development. Additionally, we expect Phase I data from our AUTO4 program, our program for the treatment of peripheral T cell lymphoma later this year as well and expect multiple next-generation development candidates to enter clinical development over the course of 2021 and into 2022. Finally, with our successful recent raise, we're in a position of strength with a cash runway into the first half of 2023.

We're happy now to take questions.

(Operator Instructions) We have our first question from the line of Eric Joseph from JPMorgan.

This is Hannah on for Eric. Just a few from us. First, in terms of primary CNS lymphoma, how should we be thinking about the size of that market? And given the limited clinical data and the indication, what about AUTO1's profile gives you comfort in its ability to show a meaningful clinical benefit? And then I have a follow-up after that.

Okay. Well, first off, thanks for joining. Appreciate it. Peripheral CNS lymphoma is a fairly tough disease. It's a disease that originates in the brain, is very similar, pretty much a form of aggressive lymphoma. And so there are a few things that we need to have with the product. The product needs to, obviously, have good access to the brain. That is certainly true for CAR-T therapies, but AUTO1, also, in particular.

Secondly, you need a high level of activity, which the program has demonstrated in the adult ALL setting. And at the same time, you would want to have a minimal amount of cytokine release that would actually generate, which is one of the hallmarks of the program so that the local concentrations could be kept low. I think those are the key features you'd be looking for in terms of the profile for a product. We think AUTO1 has actually -- or fits this profile very well.

In terms of the size of the indication, when we look at the U.S., we're looking at approximately 1,400 patients in that relapsed/refractory portion of the disease. So sizable, not quite the size, overall, as we're seeing in adult ALL, but not too far off from it either.

Okay. Great. And then also for AUTO3, what do you expect in terms of cadence of news flow from the ALEXANDER trial? Where and when might we expect additional updates from that end of it?

Right. So as I had indicated in the summary statement, is that we obviously had 4 oral presentations of the program last year. And the next data update, we're planning to do in the context of actual publication of peer review journal. So we have an ability to actually give a full overview of the data rather than the 10-minute short updates that we tend to give at the conferences. The next update is planned to the actual publication.

Okay, that's helpful. And if I could ask one more. For the upcoming AUTO1 update that you have in lymphoma coming at EHA, how can we expect safety and efficacy compare to vaccine and adult ALL to the extent that you can clarify that?

Well, we have given a -- obviously, the first 4 patients were indicated at the ASH update, which is given. And what we basically reported on is that the patients, all 4 received a metabolic complete remission and achieved that with limited adverse events. There was a low-grade cytokine release that was seen, but no high-grade cytokine release observed in these patients. So that's sort of the initial experience. And in general, you would expect a safety profile that would be less -- or actually more benign than what we're seeing in adult ALL, just given the fact that the disease is not as easily accessible as ALL is, which resides in the marrow and is a place where your T cells almost quantitatively migrate to and obviously then lead to a very high level of activity in a short period of time, which drives the adverse events we're seeing in ALL.

Obviously, in lymphoma settings, the disease obviously is much more distributed and tends to be not as easily accessible. And as a consequence, the adverse event profile is definitely going to be quite reduced compared to what we're seeing in ALL, quite similarly to what the experience is and has been with some of the programs in the space.

Your next question is from the line of Mara Goldstein from Mizuho.

Can you hear me?

Yes, we can.

Excellent. I had a couple of questions. The first is on the AUTO5 and AUTO4 program and just the advancement of AUTO5 and the bar you expect or you're expecting to use for success, given that, previously, I think you said that, that AUTO5 would only advance after you evaluated AUTO4 program. And then I'm also just curious on the AUTO3 program, understanding that your plan is to partner that program. I'm curious as to what level of support it will require in the interim and what you expect or hope your role will be with a partner, going forward, if at all.

And then secondarily, I just had a question on the ATM and whether that financial product is complete at this point, or is there still more opportunity to exercise that ATM?

Yes. So I'll start with the AUTO4/5 question. Obviously, AUTO4 is in dose escalation, and we do expect to have an understanding of the dose and activity relationship in -- from AUTO4 by the end of the year. AUTO5 is actually worked up to an IND that will be -- is planned for the -- towards the end of the year. And so, obviously, it puts us in a good position, then also building on the experience with AUTO4 to also think about the starting point in terms of dose for the explanation of AUTO5. So in that sense, we're using or planning to use information from the AUTO4 experience also to inform us for the conduct of the AUTO5 program.

As you remember, this is -- the programs are only different in the sense that they're basically seeing the same -- the very same element of the structure of the T cell receptor beta chain, but it's an inversion with 2 isoforms. It's just an inversion of 2 amino acids. So we would expect that what we learn with AUTO4 is highly likely also going to be directly applicable to AUTO5. So that's the first question.

The second question was related to AUTO3, support required going forward with the program. At this point, I think it's too early to speculate. And I think that will be, I think, a conversation at the time point when we're ready to advance the path forward for the program and a potential partner.

The third question was related to the ATM. The ATM, obviously, is in place. This was the first time the ATM was used to, basically triggered by an inbound interest and -- but the facility is placed.

Your next question is coming from the line of Ingrid Gafanhão from Kempen.

I have a couple, if I may. So you mentioned -- I don't know if I missed that, but I didn't hear you mentioning when exactly in 2021 you are planning to start the trial in CNS lymphoma. Can you remind me of that, please?

I think the word I was using was imminently. So we're expecting that to actually start at any time now.

Okay, great. And if I may, just a couple more follow-ups. You mentioned as well that the readout for AUTO4 trial was, of course, dependent on how the pandemic would affect enrollment in the trial. So I was curious if you could share just some thoughts on how that has been going so far, and if you think there is actually the chance that you can meet the H2 time line for the data?

Are you -- you mentioned AUTO4. The time you quoted was probably not related to AUTO4. The AUTO4 time line, we expect to give us data by the end of the year in terms of dose escalation. The enrollment of AUTO4 is running well. It's a study we're conducting predominantly in the U.K. and in Spain, and we're actively enrolling and treating patients at this point.

Your next question is from Matt Phipps from William Blair.

Christian, actually, I was wondering if I could ask you a question about the ALLO program. A couple of things. Is this based on the CAR construct of AUTO1? And do you plan to look at ALL or NHL? And then my question being, do you think an allo product can achieve the persistence needed for a durable response in ALL? Or is it better suited for something like NHL, where data, so far, shows you may not need the level of persistence for these cells to achieve durable responses?

Yes. So first off, we haven't guided, actually, on the construct we're using in the ALLO program. We will make that public when the program is underway. So we haven't actually guided on that yet. And we'll do that, obviously, when the study is up and running.

The second question is, I think, a very important one. I did highlight the sort of success factors that we see for CAR-T program in ALL. And one of the fundamental factors that you sort of have to get right is very long persistence. We're talking 18 months persistence or maybe longer to get into long-term benefit. That is an enormous challenge for any program on the autologous side, and it is a daunting challenge for any allogeneic program because you basically need to create an allogeneic product that does not get recognized by the patient's immune system for that period of time. We have no evidence in the space to date that this is anywhere close to being feasible.

So when I think about the disease settings, ALL is probably the most challenging disease setting to get to long-term remissions with an allogeneic program. If you try to get sort of a bridge to transplant, you may try to do -- you may try to see whether that might give you some activity. But if you want to get actually sustained responses, this is probably going to be the hardest hurdle to take.

In some of the lymphoma settings, it looks like, based on the initial experience that we've seen with (inaudible) in DLBCL that the activity could be sort of basically successful, also from a durability perspective, even if the activity would be delivered for a shorter period of time. So there's probably more of a likelihood or more of a chance with an allogeneic product to be active in certain non-Hodgkin's indications. However, the caveat there is that this may be true for a more aggressive [symptom] like the DLBCL, although not an easy hurdle to take, to be clear. But it may -- quite likely is a challenge when you look at any of the more indolent forms of non-Hodgkin's lymphoma, where we have a disease that basically, with everything we do today, can still trigger relapses after extended periods of time. So I would assume that non-Hodgkin's indications on the indolent side will quite likely require significant levels of persistence. Potentially, the aggressive forms of non-Hodgkin's lymphoma might create a bit of an opening with a shorter duration of persistence. But whether the month or so persistence we're seeing to date is anywhere close to what is needed, I think, remains to be seen.

For AUTO4, I know you touched a little bit on kind of benchmarking efficacy. But with the one patient that's been shown to date, I mean, they achieved a complete molecular response, but it wasn't durable. Based on the disease and just everything you know, do you think a lot of patients in this study will be pushed to transplant if they do achieve a deep response? Or is that -- when it's allowed in the study?

I think it's difficult to tell at this point in time. I think if you get patients into complete remissions, and these are metabolic complete remissions that we typically score in these patients, that, obviously, is a good starting point, but you need to show durability of effect. Obviously, what we have reported on was based on an extremely low level of the product, just 25 million cells, which is the entry dose in the dose escalation. And we obviously have to see where we get to as we dose escalate, and this is also what we're exploring at this point in time.

In terms of transplant, transplant is an option that at times is used. And typically, the patients that we're obviously dealing with here are patients that often, actually, have already relapsed from a transplant. And so doing second transplant is -- tends to be a lot more tricky, not too dissimilar from what you see in the ALL setting as well.

Your next question is from the line of Nick Abbott from Wells Fargo.

Just to clarify on AUTO5, is that going to be starting at trial gating on data from AUTO4, or have you seen enough to commit to the IND?

I think with regards to the nonclinical development you can do, there's no -- I don't think there's anything more I think we can really learn about the program. What we'd like to sort of understand from the AUTO4 program is where -- at what range do we see the active level of the program so that we could sort of fine-tune, actually, the entry-level for the AUTO5 study. I think that's probably the key parameter to come out. Should we have a challenging safety event as an example with AUTO4, then that may obviously have an impact on the program. But bar that, I think the primary information that we would derive from the AUTO4 study is actually understanding the likely entry point for a shortened dose escalation for AUTO5.

Okay. And then given what you're seeing on AUTO1 in the refractory ALL population, where do you go next? And in your cash runway guidance, does that allow for expansion of clinical investigation program in adult ALL, presuming that you're also looking at commercializing the product within the cash runway as well?

So when we look at the current program, obviously, the focus is on that -- on the relapsed/refractory setting, and we include -- we will have patients that will be post-relapse, post-blina or post-inotuzumab as well as patients that are -- have not yet been exposed to either 1 of the 2 agents. So it's going to be -- it's basically too slightly -- slight variations in the patient population. And that's going to be an important, obviously, aspect to sort of capture the entirety of the relapsed/refractory part of the population.

We will also explore the patients in MRD status as well within the study. At this point, this is not part of the pivotal part of the study, but we'll obviously have to see, as we go forward, whether that might become an element to be considered.

As we think then further to the opportunities in adult ALL, clearly, I think there's an interest, which we would expect to actually really get going in full steam with market approval of the product, is to move the product into early line of therapy. And there are several opportunities there that you can look at, either into sub populations, high-risk populations in the frontline setting, or then certain settings in the second-line setting as well.

So there's opportunity to grow the overall patient base within ALL and sort of create a broader footprint, not too dissimilar from, frankly, what you've seen Amgen work on with Blincyto working from the back end towards these stages, which I think gives you a pretty good sense of where you can go and what you need to show.

The -- so those are kind of -- I think probably the key aspects. Obviously, what we are doing in parallel is that we're exploring the activity of the product in adjacent indications. And I think what that gives us is a -- gives us information to then actually pick the indications to sort of add-on and sort of expand the revenue stream, building from a core of ALL and then further out. Part of that includes, obviously, the pediatric work that we're doing, which is certainly one of the areas that we have to be active in, no matter what, given the indication. And I think that is clearly an activity that will have a priority. And then as we look into the other indications, I think it's going to be driven by the data in terms of the rollout in capacity we have.

You have your next question from the line of Biren Amin from Jefferies.

On AUTO1 for the indolent NHL data expected at EHA, question, how should we be thinking about that data? Should we be looking at ZUMA-5 as context for that data set?

First of all, thanks for joining. First off, I think it's a good data set because it gives sort of an understanding of what the CAR-T can do in indolent lymphoma, particularly in that case follicular. And then it gives us, obviously, a sort of a good benchmark to look at. So it's certainly a good starting point.

I think when we look at the space, I think there are 2 things that stand out in the indolent lymphomas, and that is that, obviously, similar to DLBCL, most of the patients are not treated in transplant centers. Most patients are not treated in in-patient patient segments either. So I think what you need to find is sort of the sweet spot of activity and a very good tolerability profile.

And so those are the 2 things we're looking at and sort of to get an initial understanding of what the profile of the product would look like in this -- in non-Hodgkin's indication, maybe indolent setting.

And are you allowing patients with prior CD19 to come into that study?

Right now, actually, we conduct -- so this is a study where it's an extension of the ALLCAR study and, actually, adding additional arms to the study. This study is conducted in the U.K. with sort of limited access for patients with indolent lymphoma. We're probably starting to have first patients getting access in MCL. But at this point in time, there are no patients that are sort of post a commercially available CAR-T in the space.

Got it. And then on the CLL cohort for AUTO1, Christian, there's been limited success, I guess, with the CD19s and CLL. What gives you confidence in this cohort?

Well, CLL is interesting. As you pointed out, because it was sort of -- it's a reasonably challenging indication, I think, to crack. What we've seen, and probably the best data we've seen is the liso-cel data in the space, looking at treating patients in the presence or the absence of ibrutinib, potentially a slight improvement of activity with the ibrutinib -- basically in combination with ibrutinib.

So the fundamental challenge is sort of twofold. The first is that the overall activity, actually, has been probably below of what you would have expected to see in other lymphomas. And secondly, there's been quite significant levels of toxicity recorded still in these patients. But I think you have to sort of work on both ends of the spectrum and actually create then a sustained level of activity in these patients.

CLL is particularly challenging in the sense that, obviously, you need to be able to really also put pressure on the leukemia for an extended period of time. So I think persistence will be important, but also the overall adverse event profile, I think, will be critical to see that you can -- whether you can translate the initial effect into a long-term benefit. Those are obviously 2 properties that we see the AUTO1 program to, certainly, in ALL, demonstrate very nice level of activity, but also a good level of differentiation to other programs. And that's why we're interested in actually exploring that particular indication and see whether we can get an adequate profile there.

We don't have any further questions at this time. Sir, please continue.

All right. Well, thank you very much for joining. I appreciate you taking the time today, and we're looking forward to keeping you updated. Thank you, and have a great day.

Ladies and gentlemen, this concludes today's conference. Thank you for your participation. You may now all disconnect. Have a great day.