This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk03: Good day, and thank you for standing by, and welcome to Ottawa's Therapeutics Fourth Quarter 2021 Financial Results Conference Call. At this time, our participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you'll need to press star 1 on your telephone. Please be advised the call is being recorded. If you require any further assistance, please press star 0. I would now like to hand the conference over to your host today, Lucinda Crabtree, Senior Vice President, Finance. You may begin.
spk06: 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 Iton, 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 20F filed with the Securities and Exchange Commission on March 4th, 2021. which can be accessed on the EDCA 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 10th, 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 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 three, 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. Over to you, Christian.
spk11: 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 of 2021. If we move to slide number five, I'd like to give you a run-through of the key operational updates from 2021. First of all, our multi-center Felix study for our lead product, Obicel, 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 has shown a consistent and best-in-class efficacy and safety profile across three BALL 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 OBSEL 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 the planning approval for our new manufacturing facility in Stevenage, U.K., This 70,000 square foot facility will be leased to Otelus 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 OBSEL 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 Otalyst and is a recognized leader in the biopharmaceutical industry, having held a number of executive, operational, and commercial leadership roles. His experience is proving invaluable as we look towards the commercial launch of what we sell. Secondly, In conjunction with the Blackstone collaboration, Dr. William Young joined Otilus as a non-executive director. Bill is one of the pioneers of our industry and brings a wealth of commercial and operational experience to Otilus at a time when we're shaping the product profile and the commercial strategy of Ovisel. 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 Otilus, taking over from him on the 31st of March this year. I look forward to working with Lucy in her expanded role and would also like to thank Andrew for his many contributions to Autoless 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 six. This is just a reminder of the terms of the collaboration with Blackstone. It has strengthened our balance sheet, and as I've already mentioned, will allow us to drive the OBSEL 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 seven. 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. OBSEL is on track to be the first autoless 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-linituzumab or inituzumab treatment, as well as patients that are just progressing in a rehab setting but may not have received yet inituzumab or linituzumab. The initial FELIX Phase 1b study presented at ASH in December 2021 showed a favorable safety and efficacy profile consistent with the Olkar-19 study, in this patient population. Furthermore, as we presented in December, the duration of response from the OLCAR19 study remains highly encouraging, with morphological event-free survival for OBCL of 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 OBCL persistence in those patients as well. As I mentioned earlier, we're also exploring the activity of OB-cell beyond ALL in the context of the old CAR-19 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 OB-cell demonstrated by quantitative PCR in this patient group. We're planning additional updates from the old car extension study at the European Hematology Association meeting in June 2022. In addition to OB cell development, we're working on the next generation product candidate, which forms part of our lifecycle 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 OB cell program. This new program, called Auto-122, is currently being evaluated in pediatric patients in the CARPAL extension study. We plan to share additional clinical data on this product at EHA in June. Finally, our program Auto-4 in peripheral T-cell lymphomas 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 nine, 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 out 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 rather poor. The disease tends to progress rapidly.
spk06: I've lost the signal.
spk03: Pardon, Andrew? Yes.
spk04: I'm sorry. Have we lost Christian?
spk06: Yes, I think we have. I can't hear him.
spk04: All right, I'll continue. So we were on slide nine. So, Christian just said that 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 Blinsito, Besponsor, and Teccatus, 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 Blinsito or Teccatus. 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 priorities into a single product. We believe that is exactly what we're doing with Obicel. Obicel 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. Blinsito, targeting CD19. Inzitrimumab, targeting CD22. And Teccatus, 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 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 Teccatus. The toxicities that we're seeing with these agents are typically immunological toxicities, and with intratumorimab, also hepatic toxicities. Blinsito and Teccatus trigger cytokine release syndrome and neurotoxicity. However, the products differ in the severity of those toxicities, with Blinsito showing low levels, where Teccatus showed elevated levels of severe CRS and ICANs. With Tocatus, about 25% of the patients experience high-grade CRS, and 35% of the patients experience high-grade neurotoxicity. So if we move to slide 11, OBSL 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 Obicel is comparable to Chymriah. 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've had the opportunity to evaluate Obicel at this point in three phase one clinical trials. They cover quite a range of patients in ALL. We started with the program in pediatric patients, moving then to an adult patient population that we treated in the UK, and then the Phase 1b run-in for the pivotal study where most of the patients were recruited in the US. What we see across these three Phase 1 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 a 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 patients 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 Plincyto. 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 if we look at the data from the ORCAM-19 study, What we've been able to show is that we have exceptional persistence and there's very similar data that we could show and have published on the pediatric carpal 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 you pick up by genetic marking. 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 reach 12 months of follow-up, the event-free survival stabilizes at around 46% and stays flat up to two years and out to three years. In other words, we've been able to get these patients who are 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 The Blinzaito 18-months EFS is at 10%, and Takata's 18-months EFS is at about 25%, and we're at 46%, and we continue to stay there, whereas all of the current approved programs continue to deteriorate.
spk06: Andrew, I'll stop you there. I think Christian's back with us to turn to slide 14.
spk04: Oh, very good.
spk11: Very good. Thank you very much, Andrew. And apologies, everybody, for dropping off the line here. But 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 old course 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 BLBCL second line studies, 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 form of Lincyto has become standard of care. You can see the product has been doing well and is continually adding market share. We estimate that over 2,000 adult patients currently receive Lincyto 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 prior Blin are used as we do not view Blin as a direct competitor per se as treatment can be sequenced. More than likely, the CAR-T will be the main competitor to Obicel as it will be the only CAR-T sold product on market So we'll have established, we'll have established reuse in adult ALL. To remind, Decardus is now approved by the FDA for adult ALL, with other countries set to follow later this year. We believe that Obicel has curative potential as a standalone product and is poised to be best in class, best in class product for this indication. And Obicel, we believe, is also poised to benefit from the other trends that we've discussed, expansion of the delivery footprint, both from number of centers, giving CAR T cell therapy and use in ambulatory setting as an outpatient therapy. And moving CAR T cell therapies 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 that 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, experience, staff, and operations to the new facility, which will minimize startup risks and costs for commercial supply. As we have worked out for the supply of our pivotal study with centers across the U.S. and Europe, the location is well-suited for global supply with easy access to several international airports, including London Heathrow. The 70,000 square foot facility is being leased to OBLIS 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 unscheduled to support licensure submissions for OB-7 2023. as well as to begin supporting clinical manufacturing supply in the second half of 23 as well upon MHRA authorization. Moving to slide 18, as I indicated, we're also evaluating the products 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 OBCL in BNHL indications and also CLM last year. And in the 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've seen in ALL, in BNHL, 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 that we actually have very high levels of clinical activity. All non-Hodgkin's lymphoma patients achieved a metabolic complete remission and that gives us 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. We expanded the cohorts for the purpose of having extended follow-up on these patients in order to understand the profile and then to support the decision-making around further clinical development in those indications. We 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 had to date with OB-Cell in pediatric patients in the CAR-PAL 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 over time, and those relapses were due to loss of CD19 antigen. That's why we went back and built on this favorable profile of OBCL with its exceptional persistence as well, adding a highly potent CD22 CAR to create Auto1-22, which is a program that we're obviously moving forward from a lifecycle management perspective. Moving to slide 26, To date, we've been able to show a high degree of activity in preclinical models and did 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 CARPEL 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, given it has been presented before, but to remind you of the other four programs 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, Otolus has a wide range of technology developed over the last few years with 100 patent families under 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, Otolus has also developed, obviously, this building on this modular engineering strategy to solve challenges Particularly, not only the hematological malignancies, but also in the solid tumor settings. By engineering T-cells with multiple modules, we 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 Auto6MG 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. And this is important, particularly if you look at agents that have very high biological activity, like interleukin-12. And what we've been able to show is obviously that we can deliver interleukin-12, get the desired benefit, but we avoid the toxicity that comes along with exposure to systemic IL-12 secretion. So it highlights in a very nice way, I think, the utility of controlled expression and actually controlling expression of highly potent, potentially toxic gene products. Moving to slide 32, we have a series of next generation programs to use our modular technologies in various forms. I just wanted to reiterate our solid tumor program, all of 6NG, which is going to be in the middle of the year, which is building on multiple programming modules. And one particular module, obviously, that we are using with this program is the support of long-term persistence in the case of the CCR module that we are including in all the 6NG. So with that, we're moving to slide 33, and I will pass over to Andrew for the fourth quarter 2020 financial update. Andrew.
spk04: 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 of 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 ending December 31, 2021. and it compares to $134.9 million for the comparative period last year. Cash costs, which exclude depreciation, 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 purchased consumables used in the manufacturing process of Obisol for the Felix study. 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 related 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 end of 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 auctions 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 of costs, and that relates to, firstly, $0.8 million of expenses related to the company's commercial preparation activities, $0.6 million of employee compensation 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 of 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. Decreases due to lower cash balances held combined with lower interest rates for cash that's on 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 31-21, 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 the 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 to the corresponding period last year. Autoless estimates that its current cash on hand and anticipated milestone payments from Blackstone will extend the company's run 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 Autoless in very capable hands. And with that, I will hand back to Christian to give you an overview of the pipeline and brief outlook on expected milestones. Christian.
spk11: Thanks a lot, Andrew. Moving to slide 36. Finally, the next steps, we believe we have exciting months ahead of us with OB-Cell running through the Felix study and 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 and we plan to provide clinical updates from a number of our other programs at EHA in June of this year, namely OB-Cell in B, NHL, and CLL patients from the Old Car Extension Study, OB-Cell data in primary CNS lymphoma from the Carousel Study, Order 122 clinical data in the Extension of the Carpal Study, And clinical data from the dose escalation work we've done with auto-4 in primary T-cell lymphoma, also at EHA. This is in addition to progress across the pipeline with auto-6-MG due to enter the clinic in mid-2022 and actually auto-8 being rather imminent in terms of the start of the phase one study. Finally, as a result of our collaboration with Blackstone, we're in a strong position with a 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.
spk03: And thank you. As a reminder to ask a question, you'll need to press star 1 on your telephone. To withdraw your question, press the pound key. Please stand by. We compile the Q&A roster. And our first question. comes from Jill Plum from Needham and Company. Your line is now open.
spk12: 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 quote-unquote COVID-proof the Felix study?
spk11: All right, Bill, first of all, thanks a lot for joining. I was thinking you had more than one question, so I was waiting for the next question to come. But happy to answer the Felix question. Which I do appreciate. So with regards to the Felix study, obviously as we're getting into the fourth quarter, obviously we have very significant impact on many centers, not only the U.K., but also across the U.S., 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 U.S., 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 U.S. that are not in a position where they can actually operate clinical trials. We expect that to actually now to lessen as we get, you know, further into the year. And we certainly see an upswing kind of starting in January and then gradually moving up. I think we've done everything that is possible to, quote, unquote, you know, COVID-proof the trial. But we need to remember, you know, these patients do require significant access and support at the respective centers. And, you know, there is 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 are a 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 done what is possible, and I think we now have a very steady flow of patients as we're progressing the study.
spk12: Okay. I'm maybe moving to the pretty data-rich IHA ahead of you. Specifically for the DLDCL cohort, are we going to see additional patients in addition to those that you've already discussed?
spk11: Yes, we keep enrolling in those cohorts. Each cohort is designed for about 10 patients each, so we continue to enroll patients in the DLDCL cohort as well as the other cohorts as well. Okay.
spk12: And maybe a quick competitive question on auto-122. So, again, from a competitive standpoint, how common is a CD19 negative relapse in patients that are currently being treated with commercial CAR-2s? And is the rate similar to the one that you guys observed with your own study?
spk11: 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. When we're, however, looking into other indications, be it DLDCL 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 or CD19 loss as a driver for relapse is that obviously you have to have products that are very long persisting so you can exclude actually a potential contribution of the relapse due to potentially just loss of the CAR T cells, which is one of the drivers that can actually lead to relapse itself. So I think with OB-Cell, we have a real opportunity to evaluate that in a very stringent way, given that we have very long persistence with the product. And with that, you know, that contribution, a potential contribution of CD19 loss, I think will become very visible. obviously the initial experience that we have in our first, um, you know, experience in the old car study and the one B, uh, portion of the Felix study, obviously we've seen some, uh, CD19 negative relapses, but, uh, obviously those were limited and certainly not in the magnitude that we have seen prior in the pediatric patients.
spk10: Okay.
spk12: That's a, that's a great, uh, summary. And on auto eight, um, It looks like there's a start of a phase one 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?
spk11: We haven't updated on that. I think we're going to be talking about that when the study is up and running, and obviously we'll spend some time on that program. 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 start to talk about it more.
spk12: All right, and one last one for Andrew, because he's going to be leaving us. Are the BlackRock milestones front or back-ended?
spk04: Gil, thanks for the question. I think what we've 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.
spk12: Okay. Okay. Andrew, you will be missed. And thank you guys for taking our questions.
spk03: Thanks, Gil. Thanks a lot, Gil. Thank you. And our next question comes from Mar Goldstein from Missoula. Your line is now open.
spk01: Great. Thanks so much for taking the questions. I just wanted to ask, you know, you'll 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, you know, the all-car 19 extension cohorts and auto 122 as well? Or rather, excuse me, not auto 122, but also carousel in the CMS lymphoma?
spk11: Thanks for joining, Mara, and thanks for the question. Obviously, what we're doing in the all-car study is evaluating the profile of OB-Cell in those indications, and when we look at the respective indications, there's several, I think, aspects that matter in terms of assessing the potential of the product. One is I think for 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 that 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 to have, I think, a good level of follow-up, particularly on 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 mantle cell experience. So I think as we're going to 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 subindications. 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 of CAR-T and Obicel in that very challenging patient population. What we'll have at EHA is initial data from the initial patients that we have that were treated. And I think we're going to gain 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.
spk01: All right. Thank you so much. And, Andrew, good luck and enjoy retirement.
spk03: Thanks, Mara. Thank you. And our next question comes from Nick Addett from Wells Fargo. Your line is now open.
spk08: Terrific. Thanks for taking our questions. And my congratulations to Andrew, too. Just go back to the Stevenage facility. Obviously, it's a 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 know, you said it'll support around about 2,000 doses per year. You know, to increase that, do you expect... or to just build out the existing shell? And I have a follow-up, thanks.
spk11: Yeah, very good. Well, thanks for joining, Nick. Really appreciate it. Another early day on your side. So the Stevenage facility, obviously, you see this in the February picture. Obviously, a lot of the groundwork that's been done. The actual facility is actually built, most of it is built actually in the factory, and so they're all prefabricated modules. So As soon as the ground actually has been ready, obviously, the actual time to wreck the building is very quick. And we're starting to see now the building get off the ground in a very nice pace and smack 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 VLA file and we'll be in time to support it. In terms of increasing capacity, the current facility, as indicated, 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 currently are building that is actually available and could be used for an extension of the building, which actually will give just an extended overall operating environment that we can use in Stevenage. Now, what we will do is we'll balance, if you look longer term, the manufacturing capacity in the UK with, at some point, a second site. And that's obviously one of the things that we're looking at. very likely it will take over time to sort of consider a second site in the U.S. But that obviously is downstream and post-launch of the product. So for now, the facility actually is exactly what we need. It allows us to cover, actually, we believe, the full opportunity in the adult day-to-day setting.
spk08: Great. Thank you. So, you know, I think you've said the Felix PLA target is 2H23. Can you talk about timing for European submission, and then how do you think about partnering options for Japan or greater China, for example?
spk11: Yeah, very good question. So as we had indicated, obviously we expect full data first half of 23, which gives us an ability to drive to a BLA filing second half of 23. Now, as we're thinking through the sequencing of an opportunity of sequencing in terms of different regulatory jurisdictions, obviously the primary focus is on the BLA and the U.S. market for very obvious reasons. But there is also opportunity to potentially also take a faster path in the U.K., which is currently under exploration, under the so-called ILAP process, which is a designation we've received and 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 dissimilar 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 would 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 over time just based on the regulatory review timelines that we've 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 globe doesn't end beyond, you know, 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's not a lot of 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.
spk08: Perfect.
spk11: Thanks a lot, Christian. All right. Thanks a lot, Nick.
spk03: And thank you. And our next question comes from from Truist. Your line is now open.
spk09: Hi, this is Bill on for . We were wondering about any potential updates or clinical initiations for auto seven or the ALO program or any sort of color regarding those? Thanks.
spk11: So the other seven is certainly a program that we've pushed. We did push back from a priority perspective. The focus is on all the six NG on the solid tumor side and also actually obviously collecting and reviewing some of the data that we've seen in the space of PSMA targeting, which is obviously a mixed picture. 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 auto-7, we're pushed back behind auto-6 and G, and auto-6 and G, as we indicated, we will get the clinical study up and running middle of the year.
spk09: Thank you, appreciate it.
spk03: Thank you. And thank you. And our next question comes from Matt Pips from William and Blair. Your line is now open.
spk02: Hi, thanks for taking my questions. Christian, first, do you think the recent label update for Ticardis and ALL based on the cohort 6 data with kind of the steroid prophylactic use, you know, makes any kind of difference? as far as physician perception of that product versus a potential OBISO product?
spk11: Well, first off, thanks for joining that. You know, the use of steroids with CAR-T obviously has been, you know, certainly been quite wide. And when you look at the data presentations that we've seen from TICARDIS around steroid use, obviously that's been you know, 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, you know, quite extensive use of steroids included. So that's actually the first thing. The second is that one of the things that I think has become clear, there's a number of presentations that are out there looking particularly at the steroids used in the context of Giscarda in DLBCL, did show an impact on 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 persistence 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 the Picardas to get actually reasonable level of persistence in ALL. The 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. You know, 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 have to do to sort of actually find a way to manage the product.
spk02: Okay. Thanks. And I 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, you know, 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 handled appropriately in the part two of Felix?
spk11: Absolutely. I mean, one of the key things that we have in acute leukemia, one of the challenges is that the patients can have basically an effusion of leukemic cells from the marrow into the bloodstream. And you can actually get situations where the patients, when you look at the circulating lymphocytes in the blood, you know, you have 90 or even more percent, above 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 predominantly consists of leukemic cells, but obviously, you know, a low percentage of T cells that you collect and ultimately those that the cells were interested in from a manufacturing perspective. So what we did and we spent time on early on as we transitioned 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, 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 did 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 LeukaFreeze. 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 was 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.
spk02: Okay. And one last quick one, just to make sure, clarify here. So top-line data for Felix in the second half, is that just coming in a press release with maybe something like a response rate, and then we'll get a medical conference presentation in the first half of 2023?
spk11: I think that is 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 give an update and be clear kind of what the trial looks like in terms of outcome. But then obviously a full presentation at the medical conference is obviously 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 first half of 2023. Thanks, Christian.
spk10: Okay, thanks, Matt.
spk03: Thank you. And our next question comes from A.R. Joseph from J.P. Morgan. Your line is now open.
spk07: Good morning, good afternoon. 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 top-line readout for the end of the year, and particularly wondering if there's any flexibility in including patients from the running portion in the primary endpoint efficacy analysis. And then secondly, as it relates to carousel, I'm wondering if you could just kind of help frame the primary CNS lymphoma commercial opportunity and what the regulatory outlook might look like in an indication in terms of, you know, study size and endpoints that would facilitate or allow forward approval. Thanks.
spk11: All right. Well, thanks a lot, Eric. First off, kind of with the Felix study and whether the analysis would include the Phase 1B 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 said that obviously the look at efficacy will be the phase two portion only, which is the way that the trial was designed. And so the phase two data set is the key data set from that perspective. With regards to the primary CNS lymphoma, we're looking into that opportunity. Obviously, I've done some initial sizing, et cetera, We think it is somewhere in the range between kind of the pediatric and the adult DLL 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 a label. This is a very difficult to treat disease with very limited options once the patients have relapsed. So there is likely an opportunity with a rather tailored or focused approach. But obviously those conversations obviously have not happened at this point in time with regulators. So this is just a general outlook. 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.
spk10: Okay, that makes sense. Okay, thanks for taking the questions, Christian.
spk11: Thanks a lot, Eric.
spk03: Appreciate it. Thank you. And our next question comes from Ingrid Gafanow from Kempen. Your line is now open.
spk05: Hi, Tim. Hi, Christian. Good afternoon. I just wanted to follow up a little bit more on what we should expect for a while, so 122 updates. 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 then a longer follow-up, or will this first update already contain some information, some sort of couple of months follow-up in the first patients?
spk11: Yes, so thanks for joining in, Greig. So in Ottawa 22, we did start that work at the very start of last year. So we have patients, obviously, that have been treated. And by the time we get to the EHA, well, they've been treated and followed for 12 months or maybe slightly more than that. But also the patients, you know, were, you know, enrollment kept going into the sort of the early part of the first quarter this year, and also for those patients, we will have sort of just a limited follow-up. So I think 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 Kenrya therapy. I think that's important to keep in mind. So these are patients that you would not see in a Kenrya trial or you would not have seen and, frankly, are not commercially treated with Kenrya. 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 rates, number two, the safety profile. Also, we had a very favorable safety profile with Ovisel. We want to see what the safety profile looks like with the second generic antigen receptor included in the product. And the third area that I think is important is to get a feel for persistence. And from a fundamental question related to relapses and what might have driven relapses, whether any antigen-loss-driven relapses, obviously we won't 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, safety, persistence profiles, and I think will 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.
spk05: Right, that's clear. And if I may just have a quick follow-up on that, what could be some of the reasons why these patients were not eligible for TRIO?
spk11: Well, there are a number of potential reasons. First off, obviously, if the patient's already failed, you can't get a second time on the product. So that's one reason. But then it's also depending on where the localization of the disease is. Or there may be also elements related to comorbidities that may actually exclude you from Kymriah treatment. So those are, I think, key parameters that I think are impacting. It's being in a condition that's just not conducive for the current standard of care.
spk05: All right, that's clear. Thank you.
spk03: 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 Eiden for closing remarks.
spk11: Thank you very much. Well, thanks all for joining. Obviously, great to connect. 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 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.
spk03: this concludes today's conference call thank you for participating you may now disconnect
Disclaimer