Good day and thank you for standing by, and welcome to Autolus Therapeutics Fourth Quarter 2021 Financial Results Conference Call. At this time, all participants are in a listen-only mode. After the speaker’s presentation, there will be a question-and-answer session. .
I would now like to hand the conference over to your host today, Lucinda Crabtree, Senior Vice President Finance. You may begin..
Thank you, Justin. Good morning or good afternoon, everyone and thank you for joining us to take part in today's call on the financial results and operational highlights for the fourth quarter 2021. I am Lucinda Crabtree, Senior Vice President of Finance. With me today are Dr.
Christian Itin, our 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 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, March 10, 2022, 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 obligations 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 subsequent date 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 an overview of our operational highlights for the fourth quarter of 2021.
Andrew will then discuss the company's financial results before Christian will conclude with upcoming milestones and any other concluding comments. Finally, we will, of course, welcome your questions following our remarks. And over to you, Christian..
All right. Thank you very much, Lucy and good morning, everybody and thank you for joining us today. It's my pleasure to review our operating progress for the fourth quarter 2021. If we move to Slide number 5, I'd like to give you a run-through of the key operational updates from 2021.
First of all, our multicenter FELIX study for our lead product obe-cel is going well and we're making good progress in our mission of building a leading acute lymphoblastic leukemia company. We're expecting data from the FELIX study in the second half of the year with full data in the first half of 2023.
The program is not only designed for the treatment of acute leukemia but also has the potential applications in the broader set of non-Hodgkin's lymphoma indications and have shown a consistent and best-in-class efficacy and safety profile across three B-ALL Phase I studies in patients with a wide range of age, disease burden and prior therapies.
In November 2021, we were pleased to announce a strategic collaboration and financing agreement with Blackstone Life Sciences, who have committed to invest up to $250 million into the development of obe-cel in adult ALL, supporting the full development of the program towards commercialization with $150 million already having been received in the shape of equity and project financing.
In September, we received a planning approval for our new manufacturing facility in Stevenage, UK. This 70,000 square foot facility will be leased to Autolus and is another important step for us on our journey to becoming a fully integrated commercial company.
The facility will have an initial capacity of approximately 2,000 GMP batches per year with further scope to expand. This capacity will support the launch of obe-cel and secure global supply in the initial indications. We will go into this in more detail later in the presentation.
During the course of the year, we expanded our board with two significant appointments. Firstly, we were delighted to announce the appointment of John Johnson, as non-Executive Chairman.
John has brought a wealth of commercial oncology and business experience to Autolus and is a recognized leader in the biopharmaceutical industry having held a number of executives, operational and commercial leadership roles. His experience is proving invaluable as we look towards the commercial launch of obe-cel.
Secondly, in conjunction with the Blackstone collaboration, Dr. William Young joined Autolus, as a Non-Executive Director. Will is one of the pioneers of our industry and brings a wealth of commercial and operational experience to Autolus at a time when we're shaping the product profile and the commercial strategy of obe-cel.
In terms of other updates, Andrew Oakley is retiring from his role as CFO, with Lucinda Crabtree, who has worked in a number of roles at Autolus, taking over from him on the 31st of March this year. I look forward to working with Lucy in an expanded role and would also like to thank Andrew for his many contributions to Autolus over the years.
He leaves the company in a strong position and I wish him much happiness in the next chapter of his career. Moving on to slide 6. This is just a reminder of the terms of the collaboration of Blackstone.
It has strengthened our balance sheet and as I've already mentioned, will allow us to drive the obe-cel program and build up the commercial manufacturing capacity. Importantly, assuming all the milestones are received this collaboration supports a catch runway into 2024. With that, let's switch gears and move on to slide number 7.
2021 was a busy year as far as driving our programs and clinical updates were concerned and I'd like to give you a summary of the key program updates. Obe-cel is on track to be the first Autolus product candidate tested in a pivotal study.
As you remember, our key focus is on delivering the FELIX study in adult patients with relapsed/refractory acute lymphoblastic leukemia, with the study enrolling patients who are both, post-blinatumomab or inotuzumab treatment, as well as patients that are just progressing in a relapsed setting, but may not have received yet inotuzumab or blinatumomab.
The initial FELIX study Phase Ib study presented at ASH in December 2021, showed a favorable safety and efficacy profile consistent with the ALLCAR19 study in this patient population.
Furthermore, as we presented in December, the duration of response from the ALLCAR19 study, remains highly encouraging with morphological event-free survival for obe-cel was 46% at 24 months of follow-up, with a median follow-up of 29.3 months and patients approaching up to 42 months of durability.
We continue to see sustained obe-cel persistence in those patients as well.
As I mentioned earlier, we're also exploring the activity of obe-cel beyond ALL in the context of the ALLCAR19 extension study and the data presented at ASH demonstrated a favorable safety profile with 13 of 13 non-Hodgkin's lymphoma patients achieving complete metabolic remission.
It is also important to mention the long-term persistence of obe-cel demonstrated by quantitative PCR in this patient group. We're planning additional updates from the ALLCAR extension study at the European Hematology Association meeting in June 2022.
In addition to obe-cel development, we're working on the next-generation product candidate, which forms part of our life cycle management strategy. For this candidate, we've added a highly potent CD22 CAR on top of the CD19 CAR that is the foundation for the obe-cel program.
This new program called AUTO1/22 is currently being evaluated in pediatric patients in the CARPALL extension study. We plan to share additional clinical data on this product at EHA in June. Finally, our program AUTO4, in peripheral T-cell lymphoma has made good progress and were moved through the dose escalation.
We plan to present initial clinical data from that dose escalation trial at EHA in June as well. Moving to slide number 9, focusing specifically on adult acute lymphoblastic leukemia. There is a very high unmet medical need for these patients. ALL is a very challenging disease.
It resides in the bone marrow and it is formed and driven by cells that are very close to actual stem cells. Those cells have enormous proliferative potential and they're very challenging to manage.
Because they reside in the marrow and crowd at normal marrow cells, the patients tend to become significantly immune suppressed as a consequence of the disease itself.
The standard of care that we're using in this space is high-dose combination chemotherapies, which consists of intervals of treatment with short recovery times that are done and repeated in cycles is a horrendous type of treatment for patients to go through, the outcome however is positive from a response perspective.
About 90% of the patients achieve complete remission. The challenge however is that most of these remissions are short-lived and the patients relapse. In fact, only about 30% of the patients see longer-term benefit after the initial line of therapy. Once you relapse, the outlook is well at core. The disease tends to progress rapidly..
I have lost the signal..
Pardon.
Andrew?.
Yes..
I'm sorry..
We lost Christian?.
Yes, I think we have. I can't hear him..
Okay. I'll continue. So we were on slide 9. So Christian just said the disease tends to progress rapidly. A normal course of action is that these patients have the option of a set of targeted therapies, which include Blincyto, Besponsa and Tecartus with or without a stem cell transplant.
Overall the challenge has been with these patients that they are prone to have immunological toxicities particularly if you use immune-based therapeutic approaches like Blincyto or Tecartus. These patients are rather fragile and have a lot of co-morbidities.
You need to have a therapeutic approach that is on the one hand highly potent but on the other hand well tolerated. That's quite a tall order to combine these different set of properties into a single product. We believe that is exactly what we're doing with obe-cel.
Obe-cel has received orphan drug designations as well as designations for accelerated reviews with various regulators. So if we can move on to slide 10. Here is a quick summary of the three products that have been -- more recently have been approved.
All are targeted therapies, Blincyto targeting CD19, inotuzumab targeting CD22 and Tecartus, a CD19 CAR. What we're seeing with all of these products is a high degree of activity in terms of complete remission rates that can be achieved at a range of between the 40% to up to the 80% range.
However, the fundamental challenge has been with all these therapies to get sustained responses and that still remains elusive. As you see in the table, if we're looking at 18 months of event-free survival those numbers are relatively low. They're about 10% for Blincyto, which is the market leading product and they go up to about 25% for Tecartus.
The toxicities that we're seeing with these agents are typically immunological toxicities and with inotuzumab also hepatic toxicities. Blincyto and Tecartus trigger cytokine release syndrome and neurotoxicity.
However, the products differ in the severity of those toxicities with Blincyto showing low levels where Tecartus showed elevated levels of severe CRS and ICANS. With Tecartus about 25% of the patients experienced high grade CRS and 35% of the patients experienced high-grade neurotoxicity. So if we move to slide 11.
Obe-cel has a unique mechanism of action. It is designed to efficiently engage leukemic cells without remaining bound to the leukemic cell after the kill has been delivered.
This feature is important to minimize cytokine release avoid T cell exhaustion, maximize T cell expansion and persistence and thus maximize anti-leukemic activity while minimizing side effects.
The key technical feature driving these desirable properties is a binder to CD19 on the tip of the chimeric antigen receptor that has a fast on rate combined with a fast off-rate. And as illustrated on this slide, the on rate of obe-cel is comparable to Kymriah. However, the off-rate is approximately 100 times faster.
This translates into a big difference in the time the receptor is bound to CD19. So if we move to slide 12. We have had the opportunity to evaluate obe-cel at this point in three Phase I clinical trials. They cover quite a range of patients in ALL.
We started with the program in pediatric patients moving them to an adult patient population that we treated in the UK and then the Phase Ib running for the pivotal study where most of the patients were recruited in the US. What we see across these three Phase I studies is a very consistent outcome.
None of the patients that we have treated in these studies, which is a total of 50 patients so far have experienced any form of high-grade cytokine release syndrome. They also experienced only limited high-grade neurotoxicity and that was rapidly reversible with the steroid intervention.
As you can see in the adult population, whereby, we look at any grade line for neurotoxicity it is fairly low. It's between 13% and 20% far off from the close to 90% that we're seeing with the currently approved product in the space.
We're seeing this consistent outcome, despite a difference in the underlying patient conditions that we have in these trials.
Starting with the children, with a median age of nine years going to adults with a median age of 42 years and a wide range of tumor burden going from 21% of patients, with high tumor burden to 75% of patients with high tumor burden and also a varying degree of pretreatment with Blincyto.
What is very encouraging is the fact, that the data is highly consistent across this wide range in these patient populations. So if we turn to Slide 13, please.
So just, if you look at the data from the ALLCAR19 study, what we've been able to show is that we have exceptional persistence and is very similar data that we could show and have published on the pediatric CARPALL study. What you see on the left-hand side here, is the median persistence of the CAR-T cells.
Now look up to a time point of 24 months of follow-up. What is important, is that this is not just a faint signal that should pick up by genetic marketing, this is looking at cells in circulation using flow cytometry analysis to determine the presence of CAR-T cells. These CAR-T cells are active.
So we see continued B-cell aplasia in these patients as well. What that translates to, is what you see on the right-hand side. On the right-hand side, you see the event-free survival of these patients looking at patients in ongoing complete remission.
As the patients reached 12 months of follow-up, the event-free survival stabilizes at around 46% and stays flat up to two years and up to three years. In other words, we've been able to get these patients who are at initial relapses to then stabilize. The patients that made it beyond 12 months have stayed in complete remission.
That is very encouraging and very different. Remember I highlighted before, that the Blincyto 18 months efs is at 10% and Tecartus 18 months efs is at around 25%. And we're at 46% and we continue to stay there whereas all the currently approved programs continue to deteriorate..
Andrew ,I'll stop you there. I think Christian is back with us to turn to Slide 14..
Very good..
Really good. Thank you very much Andrew, and apologies everybody for dropping off the line here. I hope it's going to hold for now. So moving to Slide 14. In summary, we believe that the profile of the product has the potential to be transformational for adult patients.
We're building on a unique mechanism of action with a very high level of complete remission rate that shows and translates with excellent persistence into long-term event-free survival in these patients and now with a median follow-up of close to 30 months from the ALLCAR study.
We combined this very favorable profile with a very favorable safety profile with no high-grade cytokine release syndrome and very limited neurotoxicity. Turning to Slide 15. We're conducting a pivotal study at this point in time. It's a 100-patient single-arm study.
We expect to be fully enrolled as we go through the course of this year and expect to have initial data starting in the second half of this year with full data in the first half of 2023. Moving to Slide 16. I'd like to take a few minutes to take a quick look at the market as it currently presents itself.
For hematological malignancies CAR-T cell delivery is fast becoming established care and has nearly doubled in 2021. CAR-T cell therapy has had notable success in moving to earlier lines noting the DLBCL second-line study ZUMA-7 and TRANSFORM which will accelerate adoption and expansion of treatment centers.
If we look specifically at ALL redirected T cell engagement in the Blincyto has become standard of care. You can see the product has been doing well and is continually adding market share.
We estimate that over 2000 adult patients currently receive Blincyto and it continues to grow at a healthy rate at around 25% as it is benefiting both from a broader delivery footprint and moving to earlier lines in therapy.
As context though the CAR-T price that we have between the various approved products range from about $400,000 to just shy of $500,000 in the current environment. I would note that our FELIX study protocol permits Blina use as we do not view blina as a direct competitor per se as treatment can be sequenced.
More than likely, Tecartus will be the main competitive obe-cel as it will be the only CAR-T cell product on market. So we will have established for use in the adult ALL. To remind, Tecartus is now approved by the FDA for adult ALL, with other countries set to follow later this year.
We believe that obe-cel has curative potential as a standalone product, and is poised to be best-in-class product for this indication.
And obe-cel, we believe is also poised to benefit from the other trends that we've discussed as expansion and delivery footprint both from a number of centers giving CAR-T cell therapy, and use in ambulatory setting as an outpatient therapy and moving CAR-T cell therapy into earlier treatment paradigms. Switching gears to slide 17.
The manufacturing of cell therapies is complex and requires a great deal of skill and experience. As we mentioned earlier in September 2021 we announced our planning approval has been granted to build the company's new manufacturing facility in Stevenage in the UK.
This location is about a mile from our current clinical manufacturing operations at the CGT facility, and will allow us to transition our entire operation, experienced staff, and operations to the new facility, which will minimize start-up risks and costs for commercial supply.
As we have worked out for the supply of our pivotal study with centers across the US and Europe the probation is well suited for global supply with easy access to several international airports including London Heathrow.
The 70,000 foot – square foot facility is being leased to Autolus and will allow for approximately 2,000 batches a year of initial capacity with scope to expand further when needed. You will see below an image of what the facility should look like once completed and also on the right side a snapshot of the works underway in the middle of February.
The facility is on schedule to support licensure submissions for obe-cel in 2023, as well as to begin supporting clinical manufacturing supply in the second half of 2023 as well upon initially authorization. Moving to slide 18.
As I indicated, we're also evaluating the products out – the product outside of ALL in non-Hodgkin's indications and expect to provide updates on these programs over the course of this year. Moving to slide 20.
We started exploring obe-cel in B-NHL indications and also CLM last year, and in 16 patients we have reported so far we've seen a remarkably positive safety profile with no high-grade cytokine release syndrome and no patient experiencing any form of neurotoxicity.
Moving to slide 21, as we see in ALL in B-NHL, we see excellent expansion and engraftment the CAR-T cells behave very similar to what we've seen in the ALL patients. Slide 22 then shows the results have – shows results that we actually have very high levels of clinical activity.
All non-Hodgkin's lymphoma patients achieved a metabolic complete remission and that is obviously a strong basis to build on. We had one CLL patient in addition to the non-Hodgkin patients that was valuable that had a partial response with a minimal residual disease negative condition in the bone marrow.
All-in the results are obviously very encouraging. Furthermore, as you can see we have initial good durability in the follicular patients. Summarizing on slide 23. In summary, we have a very favorable starting point that, we're now exploring in a larger patient group.
They expanded the cohorts for the purpose of having extended follow-up of these patients in order to understand the profile and then to support the decision-making around further clinical development in other indications. We'll plan to have further data presentations at EHA in June this year. Switching to slide number 25.
On the right-hand table, we provide a quick summary of the basic experience that we have to date with obe-cel in pediatric patients in the CARPALL study.
The fundamental finding was that we have excellent activity no cytokine release-related severe toxicity, but we did see about half of the patients relapse or decline and those relapses were due to loss of CD19 antigen.
That's why we went back and built on this favorable profile of obe-cel with its exceptional persistence as well adding a highly potent CD22 CAR to create AUTO1/22, which is the program that we're obviously moving forward from a life cycle management perspective. Moving to slide 26.
Today, we've been able to show a high degree of activity in preclinical models and they'd obviously share some of the data at the ASH conference. Obviously, the product is highly potent and we believe has the right properties to make a difference in the pediatric patients.
This program is now obviously in clinical evaluation in an extension of the CARPALL study and we expect to update you with first actual clinical data at the EHA meeting in the middle of the year. Moving to Slide 29. We're actively exploring T cell lymphoma which is an aggressive disease with very poor prognosis for patients.
I won't dwell on this slide. The announcement presented before but to remind you the AUTO4 program is in clinical exploration and we plan to provide a clinical update – actually first clinical data from our dose escalation study at EHA this year as well. Moving to Slide 30.
When we look at the technology, obviously Autolus has a wide range of technology developed over the last few years with 100 patent families on the prosecution, which is obviously a very significant technology treasure chest that we're building on and gives us an ability to really create very specific and very detailed properties in our products.
In addition to our hematology pipeline, Autolus has also developed obviously is building on this modular engineering strategy to solve challenges, particularly not only in the hematological malignancies but also in the solid tumor settings by engineering T cells with multiple modules that can generate complex therapeutics, with multiple properties.
One of the key areas that obviously, we've been engaged in is related to the several modules that we have included into the AUTO6 NG program. Now moving to Slide 31. This is just a quick look at a new piece of technology that we just published on which actually allows us to express particular protein modules at very low levels in our CAR-T cells.
This is important, particularly if you look at patients that have very high biologic activity like interleukin-12. And what we've been able to show is obviously, that we can deliver interleukin cells get the desired benefit but we avoid the toxicity that comes along with exposure to systemic adult cells secretion.
So it highlights in a very nice, whether I think the utility of controlled expansion and actually controlling expression of highly potent potentially toxic gene products. Moving to Slide 32. We have a series of next-generation programs that use our module with technologies in various forms.
I just wanted to reiterate our solid tumor program AUTO6 NG, which is starting to be in the clinic middle of the year, which is building on multiple programming modules. And one particular module, obviously that we are using our test program is the support of long-term persistence in the case of the CCR module that we're including in AUTO6 NG.
So with that, we're moving to Slide 33, and I will pass over to Andrew for the fourth quarter 2021 financial update.
Andrew?.
Thanks, Christian and good morning or good afternoon to everyone. So we're on Slide 34 and it's my pleasure to review our financial results for the fourth quarter to December 31, 2021. So starting with our cash position. Cash at December 31, 2021, totaled $310.3 million as compared to $153.3 million at December 31, 2020.
Net total operating expenses for the 12 months ending December 31, 2021 were $165 million. That's net of grant income and license revenue of $2.3 million and that compares to net operating expenses of $168.1 million net of grant income and license revenues of $1.7 million for the same period in 2020.
Research and development expenses remained relatively flat at $134.8 million for the year ended December 31, 2021 and compares to $134.9 million for the comparative period last year. Cash costs, which exclude depreciation and amortization as well as share-based compensation increased to $121.4 million from $116.9 million.
The increase in research and development cash costs of $4.5 million consisted primarily of an increase in compensation and employment-related costs of $3.8 million, due to a combination of an increase in employee headcount to support the advancement of our product candidates in clinical development and the severance payments related to the reduction in workforce that was initiated during the first quarter of 2021.
Secondly, an increase of $2.5 million in facility costs related to continued scaling and manufacturing operations. And thirdly, an increase of $2.4 million in purchase consumables used in the manufacturing process of obe-cel for the FELIX study.
And fourth, an increase of $0.9 million in IT infrastructure and support for information systems, related to the conduct of clinical trials and manufacturing operations. And lastly, an increase of $100,000 read to cell logistics, which is offset by a reduction in clinical trial costs of $5.2 million overall.
Non-cash costs decreased to $13.4 million for the year ended December 31, 2021 from $18.1 million for the previous period last year.
The $4.7 million decrease of non-cash costs is related to a decrease of $7.7 million of share-based compensation expense as a result of a lower fair value of options recognized during the period and due to the reduction in workforce that was initiated in the first quarter last year and that was offset by a $3 million increase in depreciation expenses.
General and admin expenses decreased to $31.9 million for the year ending December 31, 2021 from $35 million for the year ending December 31, 2020. Cash costs, which as I've explained exclude depreciation as well as share-based comp, decreased to $26.7 million from $27.4 million.
There were decreases of $0.7 million related of cost and that relates to firstly, $0.8 million of expenses related to the company's commercial preparation activities, $0.6 million of employee compensation during -- due to the reduction of workforce in the first quarter of 2021 and lower retention costs.
Thirdly, $0.5 million of facilities costs and fourthly, $100,000 in general admin expenses which all of that was offset by increases in Directors and Officers insurance and IT infrastructure and support for information systems of $1 million and $0.3 million respectively.
Non-cash costs decreased to $5.2 million for the year ending December 31, 2021 from $7.6 million for the corresponding period last year.
The $2.4 million decrease in non-cash cost is mainly attributed again to lower share-based compensation expenses recognized during the period and due to the reduction in workforce that was initiated during the first quarter of 2021.
Interest income decreased to $0.3 million for the year that compares to $0.5 million for the year ending December 31, 2020. Decrease is due to lower cash balances held combined with lower interest rates for cash that's on the deposit.
Interest expense increased to $1.1 million for the year ending December 31, 2021 and that relates to the liability relating to the sale of future revenue, which arose upon entering into the collaboration and financing agreement with Blackstone.
Income tax benefit decreased to $23.9 million for the year ending December 31, 2021 from $24.2 million for the corresponding period last year. This is due to a small decrease in research and development expenditures which were qualifying for tax credits for the year.
And as R&D credits fell at a faster rate than the company's net loss before income tax, this led to a lower effective tax rate.
Research and development credits are obtained at a maximum rate of 33.35% of the company's qualifying research and development expenses and the decrease in the net credit was primarily attributable to a decrease in eligible expenditure.
The net loss attributable to ordinary shareholders was $142.1 million for the 12 months ending December 31, 2021 and that compared to $142.1 million for the same period in 2020.
The basic and diluted net loss per ordinary share for the 12 months ending December 31, 2021 totaled a loss of $1.97 compared to the basic and diluted net loss per ordinary share of $2.76 for the corresponding period last year.
Autolus estimates that its current cash on hand and anticipated milestone payments from Blackstone will extend the company's own cash runway into 2024. And with that, it would be remiss of me before I hand the call back to Christian to not thank Christian for his kind words.
I've enjoyed my time working with Christian and the management team and I certainly wish Lucy all the best. Lucy's promotion is very well-deserved and I have the utmost confidence that she will excel and I'm leaving the finance function at Autolus in very capable hands.
And with that, I will hand back to Christian to give you an overview of the pipeline and a brief outlook on expected milestones.
Christian?.
Thanks a lot Andrew. Moving to slide 36. Further the next steps, we believe we have exciting months ahead of us with obe-cel running through the FELIX study in adult ALL, delivering initial clinical data from this pivotal study later this year and with full data expected in the first half of 2023.
We've also guided that we plan to provide clinical updates from a number of our other programs at EHA in June of this year namely obe-cel in B-NHL and CLL patients from the ALLCAR extension study.
Obe-cel data in primary CNS lymphoma from the CAROUSEL study, AUTO1/22 clinical data in the extension of the CARPALL study and clinical data from the dose escalation work we've done with AUTO4 in primary T cell lymphoma also at EHA.
This is in addition to progress obviously across the pipeline with AUTO6NG to turn to the clinic in mid-2022 and actually AUTO8 being rather imminent in terms of the start of the Phase I study.
Finally as a result of our collaboration with Blackstone we're in a strong position with the cash runway as you heard from Andrew including project financing payments from Blackstone, which gets us into 2024. We're now happy to take questions..
Thank you. Our first question comes from Gil Blum from Needham & Company. Your line is now open..
Good morning and good afternoon guys. Thanks for taking our questions. Just a few from us. So first of all there were some delays on the FELIX study due to COVID.
Are you guys taking any strategic moves to “COVID proved” FELIX study?.
All right. Gil, first of all thanks a lot for joining. I was thinking you have more than one question. So I was waiting for the next question to come. I'll be happy to answer the FELIX question. So you're correct -- which I do appreciate it.
So with regard to the FELIX study, obviously, as we were getting into the fourth quarter, obviously, we had very significant impact on many centers not only in the UK but also across the US. First on the tail of the Delta surge and then basically moving straight into the Omicron surge.
What we're seeing across the centers is that there is a very significant reduction of -- and frankly loss of nursing staff that we've seen -- actually this is across Europe as well as across the US with many centers actually struggling to keep clinical trial operations going irrespective of the nature of the clinical trial.
Most centers are back online at this point, but there's still a few centers in the US that are not in a position where they can actually operate clinical trials. We expect that actually now to lessen as we get further into the year and we certainly see an upswing starting in January and then gradually moving up.
I think we've done everything that is possible to “COVID proof” the trial, but we need to remember these patients do require significant access and support at the respective centers and there requires, obviously, significant operating -- properly operating infrastructure at the center. And unfortunately that is because it's linked to staffing.
Those issues are not fast in terms of the time it takes to fix them and frankly our longer term challenge I think for many of the hospitals to actually get back their staffing levels and training levels.
But I think within the study, I think we've found what is possible and I think we now have a very steady flow of, patients as we're progressing for the study..
Okay.
And maybe moving to the new data-rich EHA ahead of you, specifically for the DLBCL cohort, are we going to see additional patients in addition to those that you've already discussed?.
Yes, we keep evolving in those cohorts. Each cohort is designed for about 10 patients each. So we continue to enroll patients in the DLBCL cohort as well as the other cohorts as well..
Okay.
And maybe a quick competitive question on, AUTO1/22, so again, from a competitive standpoint, how common is a CD19 negative relapse in patients that are currently being treated with commercial CAR-Ts? And is the rate similar to the one that you guys serve with your own study?.
It's a very good question. And I think we're still in the process of collecting data, I think across the field. And what we're seeing, I think is clearly that particularly for the pediatric ALL patients this is the predominant cause of relapse that we're seeing.
But we however, looking into other indications via DLBCL or some of the other non-Hodgkin's indications. It is clearly a contributor to relapse, but it certainly doesn't seem to be as prominent a driver for relapse. But clearly within pediatric ALL, it's the predominant driver.
One of the key things we're looking forward in terms of the data from the FELIX study is actually to see to what extent antigen loss is driving relapses in adult patients. And I think there we still don't have enough data.
And one of the key I think factors there is in order to be able to see, the impact of target negative for CD19 loss as a driver for relapse is that, obviously you have to have products that are very long positioning so you can exclude actually a potential contribution of the relapse due to potentially just loss of the CAR T cells which are one of the drivers that can actually lead to readouts itself.
So I think with obe-cel we have a real opportunity to evaluate that in a very stringent way, given that we have very long positions with the product. And with that that contribution -- potential contribution of CD19 loss, I think will become very visible.
Obviously, the initial experience that we have in our first experience in the ALLCAR study and the 1b portion of the FELIX study, obviously, we've seen some CD19 negative relapses, but obviously those were limited and certainly not in the magnitude that we have seen prior in the pediatric patients..
Okay. That's a great summary. And on AUTO8, it looks like there's a start of a Phase I in the first half.
Have we received any additional details on this program kind of the nitty-gritty of what the targets are, or did I miss this?.
We haven't updated on that. I think we're going to be -- we'll be talking about that when the study is up and running. And obviously we'll spend some time on that program. But obviously, it is -- at this point still early. And we want to make sure the program is running properly in the clinical study. And then, we'll exactly talk about it more..
All right.
And one last one for Andrew, because, he's going to be leaving us, are the BlackRock milestones front or back ended?.
Gil thanks for the question. I mean, I think, what we said is that, the milestones are related to development and regulatory milestones. So that probably just gives you an idea, in terms of when we would expect to receive them..
Okay. Okay. Andrew, you'll be missed. And thank you guys for taking my questions..
Thanks, Gil..
Thanks a lot, Gil..
Thank you. And our next question comes from Mara Goldstein with Mizuho. Your line is now open..
Okay. Thanks so much for taking my questions. I just wanted to ask you obviously have a big EHA update this year. And so, when do you think you'll be in a position to talk about potential next steps for the ALLCAR19 extension cohort and AUTO1/22 as well -- or rather, excuse me, not AUTO1/22, but also CAROUSEL and the CNS lymphoma..
Thanks for joining Mara and thanks for the question. Obviously, what we're doing in the ALLCAR study is evaluating the profile of obe-cel in dose indications.
And when we look at the respective indications at specific -- several I think aspects that matter in terms of assessing the potential of the product; one is I think all of those indications you want to see a good and very well manageable safety profile.
And I think we start to get a pretty good view on that and the consistency of the data I think is very encouraging.
The second aspect is if you want to see a high degree of clinical activity that is sustained over time and clearly as we're looking at the various indications, we do need also a certain amount of follow-up and I think we'll start as we get through the middle of the year and into the second half of the year.
Actually we have I think a good level of follow-up particularly in the follicular lymphoma patients and we're starting to build obviously also on the DLBCL patients as well and are adding on CLL and some more with mantle cell experience.
So, I think as we're going through the course of the second half of the year and get to the end of the year I think we start to get a pretty good view on the respective relative profile that we have also for the program in the respective sub-indications.
For primary CNS lymphoma, obviously, this is a smaller study that we do on the academic side together with our collaborators at UCL. And this particular program is exploring obviously the utility CAR-T obe-cel in that very challenging patient population.
What we'll have at EHA's initial data from the initial patients that we have that were treated and I think we're going to get more experience as we treat more patients particularly second half of the year as well.
But I think overall we start to get a pretty good view on the range of profile that we have in those indications middle of the year and I think when it comes to durability I think a pretty clear picture by the end of this year with the extended follow-up. .
All right. And Andrew good luck and enjoy retirement. .
Thanks Mara. .
Thank you. And our next question comes from Nick Abbott from Wells Fargo. Your line is now open..
Terrific. Thanks for taking our questions and congratulations to Andrew too. Just go back to Stevengen facility. Obviously, the gigantic hole in the ground at the moment. But so when do you expect to be able to start sort of PPQ activities? And then you said it will support around about 2,000 doses per year.
To increase that do you expect to just build out the existing shell? And I have a follow-up. Thanks..
Yes very good. Well, thanks for joining Nick. I really appreciate it. Another early day on your side. So, the Stevengen facility obviously, you see this is a February picture. Obviously, a lot of the ground work has been done. The actual facility is actually built -- most of it is still actually in the factory and to the all prefabricated modules.
So, as soon as the ground actually has been ready obviously the actual time to rec the building is very quick and we're starting to see now. The building get off the ground in a very nice pace and snack on time.
So, what we're planning to do is actually be able to actually take on the building towards the end of the year and then run the PPQ activities in the first part of 2023. So, it gives us kind of the right timeframe and sequence into the BLA file and will be in time to support it.
In terms of increase in capacity the current facility as indicated it supports about 2,000 batches a year. There's probably a bit more room to expand upwards on that by operating at a slightly higher density.
However, there is literally the site next to where we're currently building that is actually available and could be used for an extension of the building which actually just an extended overall operating environment that we can use in Stevenage. Now, what we will do is we'll balance.
If we look longer term, the manufacturing capacity in the UK with at some point the second site and that's obviously one of the things that we're looking at very likely. It will make over time to sort of consider a second site in the US, but that obviously is stand stream and post launch of the product.
So, for now the facility actually is exactly what we need and it allows us to cover -- actually we believe the full opportunity in the adult ALL setting. .
Great. Thank you.
So I think you've said the FELIX BLA target 2H 2023, can you talk about timing for European submission? And then how do you think about partnering options for Japan or Greater China for example?.
Yes, very good question. So as we had indicated obviously we expect full data at first half of 2023 which gives us an ability to drive to a BLA filing second half of 2023.
As we're thinking through the sequencing of -- an opportunity of sequencing in terms of different regulatory jurisdictions, I would say the primary focus is on the BLA and the US market for very obvious reasons.
But there's also opportunity to potentially also take a faster path in the UK, which is currently under exploration under the so-called ILAP process which is a designation we've received that gives us an opportunity to have conversations around that.
We'll see kind of what the timing looks like around that but there may be an opportunity for an accelerated path in the UK as well not to be similar from what you typically would see in the US.
We would think about the European approach in a staggered way to the US activities and we're sort of in sequence after the BLA filing consider filing in the EU as well. Typically as you -- I'm sure are well aware the review timelines tend to be longer in the EU.
So there will be, sort of, a staggered build in terms of approvals at every time just based on the regulatory review time lines that we have seen in the space. So that's sort of the role that we're currently looking at. And then you're pointing to the fact that the growth doesn't end beyond -- with the US and Europe it goes quite a bit beyond that.
And so we're clearly looking at opportunities in kind of Asia Pacific area as well and that is sort of under investigation but there is not a guidance at this point in time of when we're planning to sort of get into those areas and start to be active from a development or a commercial perspective. .
Perfect. Thanks a lot, Christian..
Right. Thanks a lot, Nick..
And thank you. Our next question comes from Asthika Goonewardene from Truist. Your line is now open.
Hi. This is Bill on for Asthika. We were wondering about any potential updates or clinical initiations for AUTO7 or the ALLO program, or any sort of color regarding those? Thanks..
Got it. So the AUTO7 is certainly a program that we pushed -- we did push back from a priority perspective and the focus is on AUTO6NG on the solid tumor side.
And also actually obviously collecting and reviewing some of the data we've seen in the space of PSMA targeting which is obviously a mixed picture and it's an area we're looking at very carefully. With regards to the ALLO program that is actually moving forward at UCL and we expect that study to start in the upcoming months.
And it's actually all ready to go at this point in time. But AUTO7 were pushed back behind AUTO6NG. And AUTO6NG as we indicated we will get the clinical study up and running middle of the year. .
Thank you. Appreciate it..
Thank you. .
And thank you. And our next question comes from Matt Phipps from William Blair. Your line is now open.
Hi. Thanks for taking my questions.
Christian first do you think the recent label update for Tecartus in ALL based on the cohort six data with kind of the steroid prophylactic use makes any kind of difference as far as physician perception of that product versus a potential obe-cel product?.
Well, first off – first, thanks for joining us. The use of steroids with CAR Ts obviously has been certainly being quite wide. And when you look at the data presentations that we've seen from Tecartus around steroid use obviously that's been quite consistently sort of being evaluated and looked at.
In fact the data we've seen on safety including the primary label obviously has already had quite extensive use steroids included. So that's actually the first thing.
The second is that one of the things that I think has become clear there is a number of presentations that are out there, looking particularly at the steroids use in the context of Tecartus in DLBCL did show an impact on the outcome of the patients and particular challenges to sustain persistence.
And certainly, that is one of the key challenges we see in ALL is that, persistence actually does matter.
And obviously, one of the key things that we have been observing with our product is physicians that goes out for two or three years and certainly, that's an area that's been more challenging for the initial product in the space and certainly, also with Tecartus to get actually a reasonable level of persistence in ALL.
More aggressive you use steroids, the more that becomes challenging. So I think it's a difficult trade-off in terms of the safety signal. High or intense steroid use has already been part of the, frankly, the treatment before. We don't think there's going to be any significant change there.
It's been pretty much what the centers had to do to sort of actually find a way to manage the drawback..
Okay. Thanks. I had asked you guys in the initial kind of FELIX data, you highlighted some difficulties or maybe differences in the quality of leukapheresis from the safety run in higher blast counts and things.
And I don't know if you can say too much on this at this point, but do you feel like the move to the industrialized process is standardized appropriately in the part two of FELIX?.
Absolutely. I mean, one of the key things that we have in acute leukemia, one of the challenges is, the patients can have basically a fusion of leukemic cells from the barrel into the bloodstream.
And you can actually get situations where the patients -- when you look at the circulating lymphocyte in the blood, you have 90% or even more percent -- about 90% of the cells being leukemic cells.
And as you can imagine, if that's where you sort of then start to actually collecting lymphocytes from, it means that your leukapheresis is predominantly consists of leukemic cells. But, obviously, a low percentage of T cell that we collect and ultimate reset the cells we're interested in from a manufacturing perspective.
So what we did and we spent time on early on, as we transition the program onto the commercial side, is to make sure that we can actually deal with a wide range of patient conditions.
So that we're actually in a position to manufacture for -- as almost all patients, and that's certainly what we've been able to, that we're actually going to include into therapy. And that's been one of the key elements really to make sure that we have an ability to include this wide range of patients and conditions.
And those changes actually dipped to the manufacturing process, turned out to actually make sure that we can manufacture for all the patients that we have been able to actually enroll in leukapheresis. And it gives us an ability to really be able to manufacture, even if the patients tend to be very advanced and in poor condition.
So in that sense it is to make sure that the bandwidth of patients we can actually, frankly, successfully manage is expanded to the maximum extent. And that was a very successful endeavor..
Okay. And one last quick one. Just to make sure I clarify here.
So topline into FELIX in second half, is that just coming in a press release with maybe something like response rate and then we'll get a medical conference presentation in the first half of 2023?.
I think, that is a fair -- that's a fair way of looking at it. You don't want to piecemeal the data too much in terms of individual bits and pieces. So it has to be sort of high-level update early on and to give an update and be clear kind of what the trial looks like in terms of outcome.
And then, obviously, a full presentation at the medical conferences. Obviously, they're the key data release, also with a lot of deep dive which will be done at that point in time. We expect that to be in the, yes, first half of 2023..
Yes. Great. Thanks, Christian..
Okay. Thanks, Matt..
Thank you. And our next question comes from Eric Joseph from JPMorgan. Your line is now open..
Good morning. Good afternoon. And thanks for taking the questions.
On FELIX, or part two of FELIX, just wanted to really just come back to your level of confidence in providing a topline read definitely in a -- for the end of the year, particularly wondering if there's any flexibility in including patients from the run-in portion in the primary endpoint efficacy analysis? And then secondly, as it relates to CAROUSEL, wondering if you could just kind of help frame the primary CNS lymphoma commercial opportunity.
And what the regulatory outlook might look like in indication in terms of study size and endpoints that would facilitate or allow for approval? Thanks..
All right. Well, thanks a lot Eric. First off, kind of with the FELIX study and whether we would – the analysis would include the Phase Ib cohort of the study. Obviously, from a safety perspective, all the patients will be included as is normally done.
From a statistical perspective, the data set that, obviously, look at efficacy will be the Phase II portion only which is the way that the trail was designed. And so the Phase II data set is the key data set from that perspective.
With regards to the primary CNS lymphoma, we're looking into that opportunity obviously have done some initial sizing et cetera. We think it is somewhere in the range between kind of the pediatric and the adult ALL opportunity.
And when we look at the regulatory path here development path, I think, if you do have a good level of activity and the national safety profile that you should have an ability with a relatively compact trial, to be able to actually drive towards the label.
These are very difficult to treat disease with very limited options once the patients have relapsed. So there is like an opportunity with a rather tailored or focused approach, but obviously those conversations, obviously, have not happened at this point in time of regulators. So this is just a general.
So, given the type of indication the backdrop that you have with the current standard of care and comparable settings of other rare forms of oncological malignancies..
Okay. That makes sense. Okay. Thanks for taking the questions, Christian..
Thanks a lot, Eric. Appreciate it..
Thank you. And our next question comes from Ingrid Gafanhão from Kempen. Your line is now open..
Hi, Christian. Good afternoon. I just wanted to follow-up a little bit more on what we should expect for AUTO1/22 update. So you mentioned, we should see some initial data at EHA and then perhaps some more data towards the end of the year.
Can you just break down what kind of – are we looking probably at response rates at EHA and a longer follow-up, or would this first update already contains an information some sort of couple of months follow-up in the first patients?.
Yes. So thanks for joining Ingrid. So AUTO1/22, we did start that work at the very start of last year. So we have patients obviously that's been treated. And by the time, we get EHA will have been treated and followed for 12 months or maybe slightly more than that.
But obviously, the patients enrollment kept going into sort of the early part of the first quarter this year and also if those patients will have just a limited follow-up. So I think with a few things to sort of kind of set expectations.
First off, the patients that we've been treating in this particular trial are patients that are not eligible for Kymriah therapy. I think that's important to keep in mind. So these are patients that you would not see in a Kymriah trial, or you would not have seen – and frankly, are not commercially treated with Kymriah.
So that's the first thing, and it also includes patients that may have failed after Kymriah as well. So this is a very tough patient population that we sort of included in this study. The first thing that, we're obviously going to be looking at are number one, response rate; number two, safety profile.
Also, we had a very favorable safety profile that with obe-cel, we want to see what the safety profile looks like with the second generic aperture receptor included in the product. And the third area that, I think is important is to get a feel for precision.
And from a fundamental question related to relapse, and what might have driven relapses whether any antigen loss-driven relapses, obviously, we will have a first view on that, but given the range of follow-up that, I indicated to you before that is probably still a bit premature to sort of have an absolutely conclusive answer to that particular question.
And I think it will be the data by the end of the year that will give us, I think, a very good view on the impact of the dual targeting approach on the potential for CD19 loss-driven relapses in those pediatric patients. So the primary update, I think, at EHA will be about basic activity, clinical activity and safety persistence profiles.
And I think we'll start to give us a feel for the impact on potential relapse, but I think the more complete picture will be the one at the end of the year..
All right. That's clear. And if I may just have a quick follow-up on that.
What could be some of the reasons that these patients were not eligible for Kymriah?.
Well, there are a number of potential reasons. First off, obviously, the patients already failed, you can't get a second time on the product. So that's one reason. But then it also depending on where the localization of the diseases, or there may be also other elements related to comorbidities that may actually exclude you from Kymriah treatment.
So those are I think key parameters that I think are impacting attention. It's being in a condition that's just not conducive for the standard -- for the current standard of care..
Right. That's clear. Thank you..
Thanks a lot, Ingrid..
And thank you. And I am showing no further questions. I would now like to turn the call back over to Dr. Christian Itin for closing remarks..
Thank you very much. Well, thanks all for joining. Obviously, great to connect. Hopefully, in the upcoming months in-person definitely getting ready for that. And I would like to thank you all for the support and we're looking forward to an exciting 2022 completely.
Obviously, putting aside everything that's happened on the political landscape and the economic landscape, I think, from an internal perspective, we're in an excellent space. And I think has a lot of opportunity for news flow, as we go through the course of this year and looking forward to keeping you updated. All right.
Thank you very much and see you soon. Bye-bye. Thank you..
This concludes today's conference call. Thank you for participating. You may now disconnect..