Autolus Therapeutics plc

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Ladies and gentlemen, and welcome to the Altalus Therapeutics full year 2022 financial results conference call and fourth quarter operational progress. As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Julia Wilson, communications consultant. Please go ahead.

Thank you, Norma. Good morning or good afternoon, everyone, and thank you for joining us to take part in today's call on the full year 2022 financial results and operational highlights for the fourth quarter 2022. I'm Julia Wilson, a communications consultant for Autolis. With me today are Dr. Christian Eytin, our Chief Executive Officer, and Dr. Lucinda Crabtree, our Chief Financial Officer. Before we begin, I would like to remind you that during today's call, we will make statements related to our business that are forward-looking under federal securities laws and the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These may include, but are not limited to, statements regarding the status of clinical trials and development timelines for our product candidates. and our expectations regarding our cash runway. These statements are subject to a variety of risks and uncertainties that could cause actual results to differ materially from expectations and reflect our views only as of today. We assume no obligation to update any such forward-looking statements. For discussion of the material risks and uncertainties that could affect our actual results, please refer to the risks identified in today's press release and our SEC filings, both available on the investor section of our website. On slide three, you will see the agenda for today, which is as follows. Christian will provide an overview of our operational highlights for the fourth quarter of 2022. Lucinda will then discuss the company's full year financial results before Christian will conclude with upcoming milestones and any other concluding comments. Finally, we will, of course, welcome your questions. Over to you, Christian.

Thank you, Julia, and good morning to you all. Thank you for joining us. It's my pleasure to review our progress for the fourth quarter 2022. Moving to slide four, we're really pleased with our program and operational progress during the fourth quarter of 2022, which is highlighted over the next two slides. Firstly, we were delighted to announce in December that the pivotal phase two Felix clinical study evaluating OB cell in relapsed refractory adult ALL patients met its primary endpoint, based on overall response rate in a preplanned interim analysis of 50 patients with morphological disease, and as verified by an independent data monitoring committee. We're another step closer to bringing this potentially innovative treatment to an underserved ALL population, and I'll delve into the data in more detail later in this presentation. This positive data triggered a $35 million milestone from our partner, Blackstone Life Sciences, earlier than anticipated, And we're planning to provide a data update on all patients treated by mid this year, most likely at ASCO, with longer follow-up planned at the end of 2023, as well as planned DLA submission to the US FDA by the end of the year. December was a busy month for us. We also had a number of clinical updates at the American Society of Hematology annual conference, including presenting longer-term follow-up data from our adult ALL patients in the old CAR-19 phase 1 study of OB-cell, showing 35% of patients in ongoing remission at 36 months of follow-up, median follow-up, with no additional anti-leukemia therapy. In addition, OB-cell continued to show high levels of clinical activity in relapsed refractory non-Hodgkin's lymphoma and chronic lymphoblastic leukemia patients, paired with a well-manageable safety profile. We were also very encouraged with the data we presented from our pediatric ALL program, the CAR-PAL phase 1 trial of OTO-122, our dual-targeting CAR-T therapy targeting CD19 and CD22, with over 80% of patients achieving a molecular complete remission with no antigen-negative relapses observed. Additionally, we provided longer-term follow-up on the Libra T1 phase 1 trial of OTO-4 in peripheral T cell lymphoma, with some patients experiencing durable metabolic CRs, including one patient up to the one-year mark post-treatment and also in continued remission. We will be providing updates on these programs over the course of this year, and we'll also be presenting data from the carousel study of OB-cell in peripheral CNS lymphoma patients, the McCarthy Phase I trial of Auto-8 in multiple myeloma patients, and finally, the Phase I trial of Auto-6 NG in neuroblastoma patients is expected to start in the next quarter. Turning to slide five, we've made some great operational progress during the quarter. Towards the end of the year, we closed a public offering, raising aggregate gross proceeds of $164 million and net proceeds after underwriting discounts and offering expenses of $152.4 million, including a partial exercise of the green shoe by the underwriters. We believe we are now well positioned financially to bring OviCell, an innovative and potentially transformative treatment, to an underserved adult DLL patient population. In 2023, we will be fully focused on submitting a BLA application at the end of the year and working towards commercial launch in 2024. As I mentioned earlier, we also received a $35 million milestone from our partner, Blackstone Life Sciences, as a result of the positive interim analysis of OBSEL in adult DLL. At the same time, we received an additional $35 million milestone from Blackstone as a result of planned activities supporting the performance and qualification of the OBSEL manufacturing process. You will recall that we signed the agreement with Blackstone at the end of 2021, a part equity and part program financing collaboration for our lead candidate, OBSEL, and we have now received $220 million of the total $250 million committed capital. We were very pleased to announce three deals, two in October 2022 and one post-period end in January 2023, which underscores what we believe is an industry-leading cell programming technology platform we have developed at Autolus. We signed an agreement with Bristol Myers Quip, granting them access to our proprietary RTRA mitoximab-induced safety switch for incorporation into a set of selected cell therapy programs. In addition, Moderna exercised an option on one of the proprietary binders being developed against an undisclosed immuno-oncology target for the delivery of pioneering messenger RNA therapeutics. This license option stems from the deal we announced with Moderna in August 2021. Finally, in January 2023, we signed an agreement with Cavaletta Bio, which allows them to incorporate the RQRA safety switch into a cell therapy program for the treatment of autoimmune disease. The total license revenue was 6.2 million in 2022, and each of these deals have the potential for additional revenue in near-term option exercise fees, milestone payments, and royalties. We continue to make steady progress in our manufacturing and CMC operations, The first phase of the build of our commercial manufacturing facility was completed with the handover of the first of three clean rooms at the end of last year. We have named this facility the Nucleus. We're now working on the qualification and validation of the Nucleus, and we remain on track for good manufacturing practice operations commencing in the second half of 2023. We're also undertaking the development work and report generation for the CMC package planned to support a BLA submission to the FDA. Finally, total cash and cash equivalent and restricted cash at the end of December were $382.8 million. With that, let's talk more about OviCell on slide number seven. OviCell has a unique mechanism of action. What's fundamentally different about our product candidate is that it has an ability to engage physiologically with the target cell. rapidly binding to the target, which delivers specificity, paired with a fast off-rate for rapid disengagement from the target cell once the kill has been delivered. This unique engagement drives maximal activity while minimizing toxicity and is at the heart of the differentiated clinical profile we are observing in acute lymphoblastic leukemia, non-Hodgkin's lymphoma patients, and chronic lymphoblastic leukemia patients. Moving on to slide number eight. Our clinical experience with Obicel and ALL shows a high overall response rate across all, sorry, population. Shows a high level of clinical activity across all indications. Our clinical experience with Obicel and ALL shows a high overall response rate across all patient populations. including a very high level of clinical activity over the longer term that we have now observed in the old car 19 study we have a median follow-up of 36 months now in this study and with a follow-up of 24 to 47 months of observation we see that 35 percent of the patients are in long-term remission after receiving ob cell and receiving no further anti-leukemia therapy The safety profile is well-manageable with low levels of high-grade CRS and ICANNs. The midsection of the slide shows the patients with long-term remissions and continued presence of CAR T cells over the entire observation period. The program is developed under RMAT, PRIME, and ILAB designations. Moving to slide nine, we completed the enrollment and dosing of a pivotal study, a study we call the FELIX study, in adult relapsed refractory ALL patients And as I mentioned, we announced in December that we have had met the primary endpoint of overall response rate in an interim analysis based on the first 50 patients followed for at least three months of follow-up. Clinical benefit in ALL will be assessed based on patients remaining in sustained complete remission. We conducted this study in 34 centers, 24 centers in the US, seven centers in the UK, three centers in Spain during the peak of the pandemic. It is important to realize that relapsed refractory adult ALL patients are highly immune suppressed, and the pandemic poses a significant added risk to them. Moreover, due to access restrictions and various other pandemic rules and regulations, we could not access our clinical trial sites for the most part of the Felix study. You can imagine end-stage ALL patients are about as difficult a patient population to work with particularly in an environment where there is a high risk of infection, and indeed, we did lose patients to COVID. In many ways, this study was more of a real-world study conducted under difficult circumstances. In addition to patient safety, every aspect of product delivery and logistics were pressure tested during this trial, with massively reduced air traffic and impact of the pandemic on our manufacturing teams. Remarkably, manufacturing for all patients from our facility in the UK turned out to be an asset also for U.S. delivery, as the long-haul flights between the U.S. to the UK had priority over U.S. and also EU domestic flights. Next, key data readout is planned for ASCO in June this year. Moving to slide number 10. This slide summarizes the announcement we made in December regarding the pre-specified interim analysis of the first 50 out of 90 patients dosed that had reached at least three months of follow-up. The primary endpoint is based on overall remission rate, which includes patients in complete remission and patients in complete remission with incomplete bone marrow recovery, or CR and CRI. The ORR was 70%. And in fact, all recent programs in ALL have used ORR as the primary endpoint in the respective studies. Safety analysis was conducted on a larger 92-patient dataset and showed an excellent profile with high-grade cytokine release experienced in less than 3% of patients and high-grade ICANNs or neurotoxicity in less than 8% of patients. ICANNs were fully reversible. And less than 25% of patients had any grade of neurotoxicity. In contrast, to approve T-cell or T-cell engaging therapies, a very unusual safety profile in this population. As I mentioned earlier, this exciting data set triggered a $35 million milestone from Blackstone. Moving to slide number 11. This slide summarized our current experience with OB-Cell across ALL. As you can see, the data are highly consistent across the various studies, both in safety and efficacy. Worth noting is that the CAR-PAL and all CAR-19 study were conducted prior to the pandemic, while both parts of the Felix study were conducted during the pandemic. Both the CAR-PAL and all CAR-19 study were conducted in the UK, while the Felix study was largely conducted in the US. What we did pick up is that the patients in the Felix study were more advanced in their disease based on tumor burden and increased presence of so-called extramedullary disease. This is, in essence, a gain of function of the leukemia that allows it to leave the bone marrow and successfully settle and grow in other organs. Patients with extramedullary disease respond poorly to any type of antileukemia therapy. Moving to slide 12 to look further into the data we presented at ASH from the old CAR-19 study. When we then look into the outcome or long-term observation from the old CAR-19 study, we're up to, obviously, with four years of follow-up, and you can see that we have a quite unusual clinical profile. The clinical benefit in these patients is the ability to convert patients into complete remission and sustain them over long periods of time. which is obviously what we're seeing for a good proportion of these patients. When you look at the SWIM plot and moving from the bottom up, we had obviously some patients that did not respond to therapy. Then we have some patients that responded but relapsed quickly. The yellow circles are patients that relapsed with so-called CD90 negative disease. In essence, the leukemia became invisible to the therapy by losing the very structure the therapy was designed to recognize. If you then go a little further up, you see three red circles. Those are patients that relapsed because the CAR T cells, the OB cell product candidate, didn't persist long enough, and patients relapsed with CD19-positive disease. Above those, you then see a group of patients that are in long-term remission between two and four years without any additional therapy. Seven out of the 20 patients, or 35%, are in continued remission without receiving any additional antileukemia therapy with median follow-up of 36 months in the range of 24 to 47 months. Every single one of these patients has persisting CAR T cells. You see one additional patient with long-term remission who received a stem cell transplant while in complete remission. Moving to slide 13. Blincyto, a T-cell-engaging CD19-targeting monoclonal bispecific antibody, has become the standard of care in relapsed refractory adult ALL over the last few years. Key to its success has been the well-manageable safety profile. Key focus from a patient management perspective is the monitoring of neurotoxicity, or ICANs, which impact 65% of patients treated with Blincyto. In contrast, Obicel had less than 25% of patients experience ICANs of any grade. High-grade CRS for Blinzaito is low, with about 5%, and Obicel seems to be similar and potentially slightly better in terms of high-grade CRS. In contrast to Blinzaito, Tecardus, a CAR-T program approved for this indication, induces high-grade cytokine release syndrome in 26% of patients, and high-grade neurotoxicity in 35% of patients, while 87% experience neurotoxicity of any grade. 40% of patients receive vasopressors. Managing such a safety profile often requires access to ICUs. Finally, inotuzumab, while active, is primarily used as a bridging therapy. Moving to slide 14. The market opportunity in relapsed refractory ALL is in fact unchanged with about 3,000 patients in high need for therapy between the U.S., Europe, and Japan. Moving to slide 15, Blincyto, the standard of care in relapsed refractory ALL, has reached sales in 2022 of $583 million with a year-over-year growth of 24%. This product is commercialized by Amgen. Currently, the product reaches about 2,000-plus adult patients with ALL, on average receiving two cycles of Plincyto. Patients with low disease burden can receive up to four cycles of Plincyto at a combined cost comparable to CAR T therapy. Key to Plincyto's market penetration is its well-manageable safety profile, which allows delivery in non-academic hospitals in addition to the academic centers. We believe that OBSEL with its high level of clinical activity, attractive safety profile, and one-time administration is well positioned to capture that opportunity. When we look overall in terms of the price level for CAR T therapies in ALL, they are in the range of $450,000 in the US. Moving to slide 16. When we look at the steps forward, first of all, we're planning to disclose the Felix data from all patients' dose in the mid-2023, likely at ASCO and also at EHA. Long-term follow-up is planned for ASH. We're targeting the BLA submission for the program towards the end of the year, MAA filing towards the end of the first quarter of 2024, and the UK filing in the second quarter of 2024. That sets us up very nicely for the key territories that we expect to be initially active in. In addition to the mature clinical data, The submission will also require data from the validation of our commercial manufacturing site. This work has been a key focus throughout the first half of 2023 and will continue into the third quarter. Importantly, our commercial manufacturing facility is set up to cover supply for approximately two-thirds of the estimated market from the start. As we're moving through 2023, we need to prepare three key areas for commercialization. creating awareness for the program through a focused medical affairs program. Second, establish the value proposition for payers in our HTA doses. And finally, third, prepare for and start center onboarding, a process that will take between nine and 15 months to get each center ready to deliver CAR-T therapy. Moving to slide 18, to talk about the broader opportunity that we see with OB-SELF. As part of the OLCAR19 extension study, we have been evaluating OB cell in relapsed refractory non-Hodgkin's lymphoma and chronic lymphoblastic leukemia patients. We see consistently very high response rates combined with a very attractive safety profile suitable for outpatient use. The data will form the basis for the selection of a second indication after ALL. In terms of the life cycle, we started to work on the next version of OB cell, which we call OTO1-22. We're looking to minimize with this product CD19 antigen loss-driven relapses with its dual targeting approach. Building an OB cell, we're adding a highly potent CD22 CAR that can recognize very low amounts of CD22 on the surface of leukemia cells. This program was initially evaluated in children who had failed chemariya or were not eligible for chemariya therapy. In this very challenging patient population, we saw an 83% molecular response rate, and none of the children relapsed with de novo CD19-negative disease. Comparing this activity to OB-cell, we would have expected a molecular CR rate of approximately 40%, maybe 50%. We're working on further streamlining the manufacturing process for Auto-122, knowing that we have an attractive lifecycle option. Timing of investment decisions in Auto-122 will be balanced with additional indication investments for OB-cells. Slide 19. Switching gears, moving on, switching gears to slide 20 as well as 21. Our technology platform allows us to engineer a range of properties into T cells to drive specificity of recognition, resilience against negative signals used by tumor cells to evade T cell attack, and providing survival signals for T cells. Our strength in T cell engineering drives our pipeline. and is also at the heart of the three collaborations reported on in 2022 and early 2023 with Moderna, BMS, and Cavaletta. On slide 22, we have a quick summary of the earlier stage programs in T-cell lymphoma with Auto 4-5, Auto 6-NG in neuroblastoma, and Auto 8 in multiple myeloma. Both Auto 4 and Auto 8 are in phase one clinical studies, and Auto 6-NG is expected to start phase one in the next quarter. Moving to slide 23. T-cell lymphoma has a very high medical need, quite similar to BALL. In fact, when you look at the NCCN guidelines, it basically says that once you're through the frontline therapy and fail, you have to go on a clinical trial. Moving to slide 24. With its unique targeting approach, Auto4 starts to show meaningful clinical impact at the higher dose levels that we have evaluated. The first metabolic CRs are reaching one year post-treatment and we continue to follow those patients. In addition, we have streamlined the manufacturing process and are exploring the activity in an additional cohort and we're planning to report on that outcome later in 2023. Moving to slide 26 to talk about manufacturing. Cell manufacturing is at the core of any autologous cell therapy, developing a highly reliable, robust, and economical process is critical for the success of any program. In addition, we have to be able to deliver product at scale and matching the capacity to the size of the medical need in its indication, and it is important to be able to do that to have a successful rollout of your therapy. Building on the robust and well-corrected process used to manufacture for the Felix clinical study, We're standing up our commercial cell manufacturing facility called the Nucleus about a mile away from the clinical trial manufacturing site we had used for the study. This proximity is important as we'll be able to move our entire staff to the new facility, and in fact, many of them are already in the process of validating the Nucleus facility. The capacity of the Nucleus in its initial setup is 2,000 patients per batches per year, or about two-thirds of the adult ALL market size in terms of capacity. The nucleus has been a fantastic project to realize with an innovative design and about 75% off-site building to accelerate the build while maximizing the quality of the build. So with that, I would like to turn to slide 28 and pass the call over to Lucinda for our fiscal year 2022 financial update. Lucy?

Thanks, Christian. Good morning or good afternoon to everyone. It's my pleasure to review our financial results for the fiscal year to December 31st, 2022. Cash and cash equivalents and restricted cash at December 31st, 2022 totaled $382.8 million, as compared to $310.7 million at December 31st, 2021. Net total operating expenses for the 12 months ended December 31st, 2022 were $168 million, net of grant income and licence revenue of $6.4 million. as compared to total operating expenses of $165 million, net of grant income and licence revenue of $2.3 million for the same period in 2021. Research and development expenses increased by $7.2 million to $142 million for the year ended December 31st, 2022, from $134.8 million for the year ended December 31st, 2021. This was primarily due to the following. An increase of $11.6 million in clinical costs and manufacturing costs, primarily relating to our O2Cell clinical product candidates. An increase of $0.4 million in legal fees and professional consulting fees in relation to our R&D activities. An increase of $0.2 million related to information technology infrastructure and support for information systems related to the conduct of clinical trials and manufacturing operations. an increase of $0.2 million in cell logistics costs, a decrease of $3.7 million in facilities costs related to the termination and closure of our US manufacturing facility in 2021 and a shift in our overall manufacturing strategy, a decrease of $0.9 million in depreciation and amortization related to property and equipment and intangible assets, and finally, a decrease of $0.6 million in salaries and other employment costs, including share-based compensation expenses, which is mainly due to lower exchange rates used upon consolidation for the year ended December 31st, 2022, compared to the year ended 31st, 2021. And this was offset by an increase in employees engaged in R&D activities. General and administrative expenses remain consistent at $31.9 million for the year ended December 31st, 2022 and 2021, respectively, primarily due to the following. An increase of $1.4 million in salaries and other employment costs, including share-based compensation expenses, mainly driven by an increase in the average number of employees engaged in G&A activities. An increase of $0.3 million, primarily related to information technology costs. A net increase of $0.1 million in legal fees and professional consulting fees in relation to our G&A activities, which was offset against lower D&O insurance, director and officer insurance. a decrease of $1 million of commercial preparation costs due to the timing of related activities, a decrease of $0.4 million in facilities costs related to the termination of certain lease agreements in the prior year, and a decrease of $0.4 million in depreciation and amortization related to property and equipment and intangible assets. Interest income increased to $1.7 million for the year ended December 31st, 2022, compared to $0.3 million for the year ended December 31st, 2021. The increase in interest income of $1.4 million primarily relates to the increase in interest rates on our interest-bearing bank accounts and short-term investments during the year ended December 31st, 2022 compared to 2021. Interest expense increased to $8.9 million for the year ended December 31st, 2022 as compared to interest expense of $1.1 million for the year ended December 31st, 2021. Interest expense is primarily related to the liability for future royalties and sales milestones, which arose upon the execution of our strategic collaboration and financing agreement with Blackstone in November 2021. The increase in interest expense for the year ended December 31st, 2022 is primarily driven by the full year of the liability related to the Blackstone collaboration in 2022 compared to a partial year liability accrued in 2021. Other income or expense increased to an income of $2 million for the year ended December 31st, 2022 from expense of $1 million for the year ended December 31st, 2021. During the year ended December 31st, 2022, we recognised a foreign exchange gain of $1.7 million, a sublease income of $0.2 million, another income of $0.1 million. This compares to an expense of 0.1 million dollars as I mentioned for the year ended December 31st 2021 which included a foreign exchange loss of 2.2 million dollars offset by a gain on lease terminations of 2 million dollars and other income of 0.1 million dollars. Income tax benefit increased to 24.4 million dollars for the year ended December 31st 2022 from 23.9 million dollars for the preceding year ended December 31st, 2021, due to an increase in qualifying research and development expenditures for the period. Net loss attributable to ordinary shareholders was $148.8 million for the 12 months ended December 31st, 2022, and this compares to $142.1 million for the same period in 2021. The basic and diluted net loss for ordinary share for the 12 months ended December 31st, totaled $1.57, compared to a basic and diluted net loss for ordinary share of $1.97 for the 12 months ended December 31st, 2021. Finally, Autolis estimates that its current cash and cash equivalents on hand and anticipated project financing payments from Blackstone will extend the company's runway into 2025. And now back to Christian to give you a brief outlook on expected milestones. Christian.

Thanks, Lucy. Moving to slide 30. Finally, we think we have an exciting year ahead of us. Key focus is on getting OBSL into the regulatory process with BLA filing targeted towards the end of the year, followed by filings in Europe in the first half of next year. Next up are the planned Felix data presentations mid-year 2023. In addition, we're preparing for commercial product supply and launch readiness. Finally, we also expect to provide updates on the pipeline programs with additional data and follow-up during the year And with our key programs unpartnered at this stage, we have opportunity for setting up collaborations. Moving to slide 31. So with that, we believe we're at a very interesting point with the company. We've got the cash to deliver a very significant value step. We got the data to show that with Obicel, we have a differentiated product profile that addresses the high medical need with limited competition and with possibly a transformational outcome. Alongside that, we have additional opportunities for overselling broader indications and a valuable pipeline of other oncology programs. As I mentioned, we're excited about our manufacturing facility, and we have a strong technology foundation validated by our collaborators, BMS, Moderna, Cavaletta, and we look to do more deals of that nature in the future. With that, thank you very much, and we're happy to take questions.

Thank you. To ask a question, you'll need to press star 11 on your telephone. To withdraw your question, please press star 11 again. Please wait for your name to be announced. Please stand by while we compile the Q&A roster. One moment for our first question. Our first question comes from the line of Gil Bloom with Needham & Company. Your line is now open.

Good morning and good afternoon, and thanks for taking our questions. Just the first one on the data that was published from the FELIX study. So, there appear to be a slightly higher incidence of grade 3 CRS in ICANNs than kind of earlier studies. Now, given that autolysis goal is to have oversell administered in the community setting, how do you think physicians will adjust to levels of high-grade AEs?

Gil, first of all, thanks a lot for joining. Really good question. So I think it's important when we put the data in perspective. What we did show is that we have less than 3% high-grade CRS and we have less than 8% ICANNs. This is a level of grade three events for both types of adverse events. That is at or below the level of purple in cycle, which is currently used in non-academic centers. And so we believe that actually the profile is very well suited and matches the experience actually already established with the standard of care in those centers. So we believe the data is very well suited and supportive of that broader use of the product.

Yeah, that's very helpful. And another question about the filing. So what data do you expect to include in your BLA? I mean, you're going to have additional data by the filing date, including ORR and the duration of response, but will you also be including data from your MRD positive cohort?

So, really good question. So, first of all, in terms of our, you know, of demonstrated clinical benefits in the morphological cohort, which are patients that have more than 5% disease burden at the time of inclusion into the study, the focus is to demonstrate that it can actually convert these patients into complete remissions. that are sustained over time. So what you will have to look at is CRs with a limited, a minimal level of follow-up to actually establish, in fact, an appropriate level of clinical benefit. So time-dependent outcomes are absolutely a critical parameter that will have to go into a BLA and will be at the core of the assessment of clinical benefit for the product. Second, of course, the safety profile was then a key part of the assessment to understand actually the benefit-risk ratio that you have with the product, which is obviously a very key parameter to understand the suitability of the product in any given indication. With regards to the focus, when you think about the review, it really will be focused initially on the patients that have morphological disease. We obviously have also assessed mineral residual disease in these patients, the level of MRD signals that we have in the patients, et cetera. But the inclusion criteria are patients with morphological disease. The work that we do to expand the knowledge of the properties of the product across the entirety of disease burden, which includes, as you pointed out, also patients with mineral residual disease, is a data set that obviously is being generated, but it is also a data set that is not going to be part of the initial filing in terms of, it will go into safety, but it is not an aspect of the efficacy evaluation for the initial filing that we're planning.

Thank you for the clarification. And last one from us, you did mention that from your scientific collaborator, there may be some data on multiple myeloma. What do you think the gating factor would be for further development of that program, given how crowded the market is? Thank you.

Yeah, very good question. So what you're referring to is the AutoAid program that we're working on with our colleagues on the academic side. We're currently running a phase one clinical trial to evaluate the activity of AutoAid in relapsed refractory multiple myeloma patients. I think we're at an interesting spot with regards to the CAR T therapies in multiple myeloma. We have obviously seen very nice levels of activity with the two approved products in the space, but there is also a very high unmet need and at this point still a remarkable inability to meet the demand in this indication, and it is likely going to continue for quite some time. So with regards to what we're looking to see with the program, we also want to see a very high level of complete remissions in these patients combined with deep molecular remissions. And at the same time, obviously, we're looking at the safety profile. We clearly want to see a very significant level of clinical activity in these patients as a basis to consider taking the program forward. And if we're at that point, you know, clearly would anticipate that this would make sense to do in a partnership.

Okay. Thank you, Gail.

Thank you. One moment for our next question. Our next question comes from the line of Mara Goldstein with Mizuho Group.

Your line is open.

Great. Thanks so much for taking the questions. First of all, on the multiple myeloma data that you do anticipate having this year, can you just give us some element of just the scope of that number of patients and what exactly we should be prepared to be looking at? And then I also wanted to ask on Obicel and thinking forward from a competitive perspective, Is a competitive go-to-market strategy, you know, versus Blinzaito or Tocardis? Can you help us understand how you plan to position Obacel?

Yep. Hi, Myra. Thanks a lot for the two questions. So the first question was related to the AutoAID study. The AutoAID study is a small phase one clinical study, so we're looking at around 10 patients. as sort of the initial experience, and then we'll take it from there. So it's going to be initial look at the profile of the product in that initial set of patients. Now, with regards to Obicel, what we're expecting to go for is obviously a positioning of the product in the relapsed refractory setting, whether patients have had already received Blinzide or are post-Blinzide dome. And I think that is sort of obviously what the current study actually is evaluating, is patients that are in very advanced disease and with a portion having had Blenzyte or in etuzumab or in a portion who didn't. So you're looking to position the product both in parallel or after Blenzyte therapy. Obviously, the Ticardis obviously is positioned in that exact same way, so it would be the same type of positioning that we would expect for the program.

Okay, thank you.

Thanks, Mara.

Thank you.

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

Your line is now open.

Hi, Christian. Thanks for taking my question. At the recent European CAR-T meeting, Kite or Gilead presented some long-term follow-up from Zuma 3 with Tecardis. And, you know, it shows very few patients really remaining in CR even beyond two years. And so it's a pretty big contrast to the data you presented at ASH from a follow-up with Alcar-19, which shows, I don't know, 35%, 40% of patients still in CR at three years. So do you expect the Felix data to recapitulate the Alcar-19 durability, given you've talked about a little bit tougher to treat patient populations with extramodular disease and such? And I guess just how do you kind of get that durability message across to physicians in your kind of education process?

So really good question. Thanks for joining, Matt. It's really what you're pointing to is really kind of the, I think what we believe was really remarkable data from our initial evaluation of OB cell in this patient group. And obviously, as you pointed out, what we did see is a stabilization of our long-term durability curves, et cetera, with, you know, patients staying in sustained remissions about, as you pointed out, by 35% of the patients being in that category. So that is a remarkable outcome, and it's clearly something that, you know, has not been possible when I developed with my old team, Blinzaito, and has not been shown, clearly not been shown for Ticardis either. So what we're looking, what we're expecting to see with, oh, we said also the Felix study is that we also see a similar shape of the curve, where exactly that stabilization will ultimately occur. I think that's too early to tell. We don't have enough follow-up in the study at this point in time. But that is what we're looking for, and that's what we expect to see. Whether it's going to be the exact same level or a slightly different level, we do not know at this point in time. And as you pointed out, obviously one of the things that we do have um had in terms of inclusion into the studies obviously patients that certainly in that you know initial data set that we presented that had you know pretty significant uh levels of uh disease burden as well as extramedullary disease which frankly was not too much a surprise given that that first 50 patient data set really was truly peak pandemic um and so you know we'll see obviously what the full data set looks like but you know we're obviously expecting to see the same shape of the curve. And at this point in time, we can't exactly say where that's actually going to come out. That requires long-term follow-up. The fact that we saw the persistence data track what we had seen before, I think, is very encouraging, because obviously that was a clear correlation that we did see that all these patients that had long-term outcomes also had long-term persisting CAR T-cells. And the shape, when you look at persistence coming out from the trial, as we had indicated from the interim analysis, was tracking the all-car persistence curve. So that is encouraging. I think it's sort of the lead indicator, but obviously requires long follow-up to sort of be clear about where exactly we might be landing.

Okay. Can I also ask, what At what point do you request a pre-BLA meeting this year? Is that something you do after kind of the ASCO update?

So it's a really good question. So I think what you want to do at the time you go for a pre-BLA meeting is you want to actually have, you know, the data with sufficient level of follow-up so you have a very clear positioning around the outcome that it can actually present and discuss with the agency. And obviously the data we're gonna go with into ASCO, I think will start to give us, I think, a good level of observation.

So we would expect that this is going to be an interaction post-ASCO.

Okay, good, thanks, Christian. Okay, thanks a lot, Matt.

Thank you, one moment for our next question. Our next question comes from Kelly Shi with Jefferies. Your line is now open.

Congrats on the progress, and thank you for taking my question. Regarding the baseline for patients enrolled in FLEX trials, does it appear consistent with phase 1B cohort under a fraction of patients with greater than 20% of bone marrow blasts? And also, will we be able to provide more information to such as patients with the CNS disease and the actual medullary disease presence on the PHYLEX trial. Thank you. I also have a follow-up.

Okay, so thanks for joining, Kelly. Nice to have you on the call. First of all, in terms of the patient population, overall, obviously, the patient population is close and very close to what we've been seeing in the phase one portion of the study. And What we also expect to see is obviously some variability as we're sort of going through the peak pandemic in the study as well. So we're close. We may actually have seen even a bit of a worsening after that. And if you look at the ORR, obviously small numbers, but it went from 75 to 70%, which could be indicative of a slightly worse population. So that is sort of, I think, where we are. We'll obviously gonna present that in detail, the underlying patient characteristics, et cetera, at the full data presentation. It's going to be also an important piece of information, I think, will help to put the data into the appropriate level of perspective as well. So that's sort of the answer to the first question.

What was the second question?

Thank you. Super helpful. So my second question is, given the differentiated profile, especially on safety front of auto ones, Do you consider exploring the opportunity in autoimmune indications, such as lupus, given that some proof of concept data has been available?

Thanks. Thanks for the question. Well, what you're pointing to is a really remarkable data set that was developed by Andreas Mackensen and his team at the University of Erlangen. who've done a fantastic job evaluating the utility of a CD19 CAR-T approach in patients with refractory systemic lupus. The outcome of the data was quite remarkable. It's an ancient medicine paper published at the end of last year. We know the team actually had also worked with the team at the early stages of incited development, so way back, almost 20 years back. Really good data set. We believe, obviously, that, you know, Obicel has a remarkable profile, obviously, now with a lot of data around the safety of the program and clearly has an absolute outstanding safety profile, which is important when you think about use in autoimmune disease. And the other aspect, of course, is that, as we all learned in this space, is the fundamental tricky part in this with autologous CAR-T therapies is you actually have to have an ability to manufacture at scale and do that at quality and economically. And obviously that's one of the key things we have been developing for OBSEL for its initial application in ALL. So absolutely we're following that field very closely. We think it is a very attractive potential future use of programs that are very safe and very active, and we believe Obicel fits that very well.

Thank you. Thank you.

And our next question comes from the line of James Shin with Wells Fargo. Your line is open.

Good morning and afternoon, guys. Just a couple from our end. I just want to dig a little deeper into the positioning of Obicel. So do you envision ObaCell could be positioned ahead of Blincyto at some point? And is there a future study exploring this? And then on a related matter, I mean, cell therapy as a whole has started to make good headway to the earlier with a couple oncologists. Seems there's some regulatory hurdles, namely the FACT immune effector cell accreditation that makes cell therapy entering the community setting a little bit difficult or intensive. Any thoughts there? Really appreciate it.

Yeah, well, first of all, thanks for joining James. And I think, you know, a very interesting question. So, first of all, in terms of sequencing, you know, at this point in time, obviously, Blincyto is approved both in the relaxor refractory setting as well as also in patients that have mineral residual disease and that are basically in CR1 or later. So in essence, it's patients that have gone through frontline therapy with still remaining residual disease. They're technically in complete remission, but they still have measurable leukemia cells at low levels, hence minimal residual disease. And so the product obviously has labels in those two settings and obviously has been evaluated now as part of the frontline therapy. So in that sense, split-cyto will have a place in this earlier part of the treatment scheme, and we expect it to just sort of move up into that earlier setting. Now, what we see from the CARTUS approval is that the CARTUS was approved for relapsed refractory patients without actually defining, you know, is this a second, a third line, or a fourth line. Actually, it's any relapsed refractory setting. And so, we would expect that the OB cell would have the same type of scope initially. And obviously, with the work we do on minimal residual disease and evaluating the activity of the program there, I think should allow us to eventually position the program similar to the way that when Zyko is positioned. But that obviously takes time to sort of actually move up in terms of the lines of therapy. So I think that's the first part of the question. The second part of the question was more around how do you actually position CAR T therapy outside of the academic centers considering that you need a level of training or accreditation of those centers to be able to actually deliver the product. And I think what we need to understand is that particularly with OVCell, we do obviously have a very, very similar profile to incite them. In fact, in patients with low disease burden, obviously, we do have an even better profile that we've shown in these end-stage high tumor burden patients that we obviously quoted in our interim analysis. So when you look at that population that has particularly lower disease burden, but even the one that we have treated now, the adverse event profile that we have in these patients is exactly what the physicians today do manage with Blinzaito. The same level of higher-grade CRS. In fact, it's a little less than what Blinzaito has, and it's actually less neurotoxicity than what you see with Blinzaito. What's very important in that context is that obviously when you look at the overall level of neurotoxicity, it's in about two-thirds of the patients have some level of neurotoxicity with Plincyto, which requires you to monitor the patient, to observe them, et cetera, and make sure that you stay on top of it. What we have with OviCell in a more advanced patient population, because obviously we include Plincyto failures, in the FELIX study. We actually have a little more than 20% of patients that have some form of neurotoxicity, so it's actually substantially less. So the actual monitoring level is less than the burden that we have, and with that, we believe there's an opportunity to actually manage this, and with the experience on BlitzSight, we should be able to manage this in non-academic hospitals and associated potentially outpatient settings, stand-by. But that is sort of where that is now. In terms of the ability to deliver CAR-T therapy, there's obviously a level of not only patient management that's required, which obviously is covered very well with the experience on BlinPsycho, but it is also obviously requires you to actually handle the cells and manage the cells as part of the therapeutic approach, and that requires a level of training that obviously needs to be put in place. And we believe that that is a possibility for non-academic hospitals. And then we have to see how further out you might actually be able to go. But I think this gives you a very good penetration and ability to reach the ALL population with this profile, as we see and basically demonstrated through the insights already.

Thank you.

Thank you. One moment.

And our next question comes from the line of Sebastian van Schoot with Van and Scott Kemper. Your line is open.

Hi, good morning and good afternoon everyone. It's Sebastian van Schoot from van Schoot Kempen. No worries. Congrats on the project. I was just wondering for the opportunity of OB cell and other indications beyond AOL. Will there be additional updates on the ALCAR study for the other indications with additional patients? And are there any of these indications that you believe would allow for an accelerated approval pathway after additional data can show the same level of efficacy as this goes as last year? And then you also spoke a little bit about the life cycle management with auto-122. Can you expand on your thinking on the possibility to continue development of auto-122 beyond the pediatric indication into adult hematologic indications? Thank you.

Thanks, Sebastian. Thanks for joining. So when we look at the opportunity that we see with OBSEL, obviously what the product is, has a remarkable profile is to basically remove the B-cell compartment, both on malignant cells as well as healthy cells, and do that with a very good safety profile. So that's the basic property of the product. Where that is suitable, obviously, is in leukemia. It is in non-Hodgkin's lymphoma, which is what we're evaluating, and CLL, what we're evaluating as part of the old CAR-9-T study. And then, as Kelly was pointing out, there's also certain applications in the autoimmune space where that might become quite interesting, and some delete data would indicate that you might even be transformational in those settings. So this is sort of the range I think you have in terms of opportunity, significant while on the oncology side, but also one that starts to build up also in the autoimmune side. So that's the range. And now the question of choice. What we're seeing in our old COVID-19 study is really that we're having a very high level of clinical activity across the entire range of these indications. And that gives us a lot of confidence in terms of the overall quality of the product. In terms of the individual indications, obviously, you have opportunities looking at that. DLDCL is an example where we see very high levels of complete remissions that are sustained. We haven't seen any relapses today in that cohort, which is quite remarkable. There are also obviously very interesting data in mantle cell as well as in C-level that we have seen. Now, all those indications are opportunities to develop in segments of the indication, which allows it to move relatively quickly and with an accelerated path. And then depending on the indication you look at, you also may then want to, as you sort of go for a last line setting, will want to actually start looking at an earlier line study as well, which then typically would be a randomized control study in that earlier line, and would want to move on that reasonably, in a reasonable sort of time relation to your last line setting. So that's sort of the opportunity, and we're looking at these, and also the data from the old CAR data, old car study does give us, I think, a very nice basis to sort of develop the right options for the investment. You then also asked about how in that conversation how Auto 122 fits. And as we indicated, we obviously do know now with Auto 122 that we have a very active program. It appears to do exactly what we want in terms of avoiding the occurrence of target negative relapses, which is the key thing that obviously you'd be looking to address. And where we know that it's particularly important is obviously acute leukemia. There's been initially reports that there is a certain proportion of patients that do actually show CD19 negative relapses in the context of diffuse large B-cell lymphoma. There haven't been as many reports more recently. In our own hands and with OB-cells, we haven't seen CD19-negative relapses, nor did we with our planter program. So whether or not that is a major issue to actually address in those indications, I think is unclear at this point in time. And I think that is sort of one of the questions I think we'll look into in terms of the ability to broaden the utility of the dual targeting approach into additional indications. But where it's very clear is that in ALL, that is certainly a driver for relapse, both for children as well as for adult patients. at some point it makes sense to consider that program to move into the succession of OBCEL in the acute leukemia setting as well. So that's sort of I think in terms of the range as well as the way we're thinking about it. And ultimately it's a set of investment decisions and it's a question of sequencing those investments. And I think the priority will first be on actually broadening the opportunity for OBCEL and then in a second step, actually then moving forward with O2-122 in terms of the actual life cycle to oversell.

Great. Thank you very much. Thanks, Sebastian.

Thank you. One moment.

And one moment. Our last question comes from Africa. Guna Warding with Truist. Your line is open.

Hi, this is Karina for Astica. Just have a few questions on pricing. With the filing due by year-end, how are you guys thinking to price Obicel? And can you also discuss some preliminary feedback you have received from payers in the U.S. and Europe? And also, is there any potential for your pricing power change with detailed data at ASCO? Thank you.

Sorry, Karina, I didn't get the last part of the question.

The pricing power with the next updated ASCO.

Oh, I see. Okay. Thank you. Well, first of all, thanks for joining, Karina. Interesting questions related to pricing. I think what we've been seeing across the states is two dimensions. First of all, we're having in ALL specifically, obviously with Blinzyco and the use of Blinzyco in patients with lower disease burden, we also do see a use of up to four cycles in those patients, which, you know, is basically getting the price for that product into the range of between $400,000 and $500,000 per patient in the US. So that's sort of one benchmark which is standard of care and kind of what bracket that is. When you then look on the approved CAR T therapy in ALL, that is in the range of $450,000 during the course, expected to be during the course of this year. So that's sort of the second sort of I think, a bracket that we're seeing in the U.S. And we would expect that we would be pricing in a similar range. Obviously, we believe that we do have a product that actually allows you to be more efficient from a cost perspective because the product should induce less toxicity, require less patient management. And with that, I think there should be a good health economic argument supporting the use of Obicel in addition to, obviously, its clinical properties. With regards to Europe, we're obviously seeing across the board with CAR-T therapies that the prices are sort of starting in the range of where the U.S. prices are with some level of discount depending on the jurisdictions you're looking at and the indication that the products are delivered in. So that is more variable, and we'll see how that develops over the upcoming period of time. And so we'll obviously keep you updated how that field evolves over time, but I think this is where this stands and the current expectations is that we would consider to be somewhere in line with what we've been seeing in the space. In terms of data flow, I think we're going to have a very interesting data flow as we go through this year. Obviously, at ASCO, obviously data from all the patients that were dosed, but also still a limited follow-up on some of the patients that I think are focused on a lot of their descriptions of the patients, the basic activity, the behavior of the product in every aspect. And then I think as we go to ASH and then even later into 2024, I think obviously much more longer-term follow-up, which I think will flow obviously as an important parameter into the HTA assessments and value assessments that will be conducted by the payers.

So that's, I think, where we are with those projects.

So just, do you think the longer-term follow-up is going to push pricing higher?

Well, first of all, the impact of the longer-term follow-up and showing an impact on longer-term follow-up, I think, is obviously strengthening your value argument for the product. So I think it will clearly make a very strong case for using the product based on more patients achieving long-term outcome. And I think that is certainly going to be a key parameter that will drive the value assessment by anyone who would look at the program. So it will definitely influence the overall assessment. To what extent that would influence pricing, I think it's premature to discuss.

Okay, thank you.

Thank you, Karina.

Thank you. At this time, I'd like to turn the call back over to Mr. Christian Eaton for closing remarks.

Well, first of all, thanks, everybody, for joining. Obviously, it was great to be able to update you on a very exciting fourth quarter that we're running through. We're in, I think, a very important stretch as we go through the course of this year, getting the product ready for filings, and I think, obviously, a real opportunity for substantive data updates as we go through the course of the year with the next ones as expected for the Meteor section. So really looking forward to meeting you, hopefully in person, and updating you on the program along those venues, and wishing you a successful first half of the year. And then I think for all of us, I think a more relaxed second half of the year, with some hope that some of the big picture items hopefully will start to turn into a more favorable environment. So with that, I'd like to thank you all and wish you a good day.

Ladies and gentlemen, thank you for your participation. And due to time limitation, we were conscious of the time and we weren't able to reach out to everyone. So management will connect with everyone that weren't able to connect to the call after the call. Thank you very much. Please enjoy your day. You may now disconnect.

The conference will begin shortly. To raise and lower your hand during Q&A, you can dial star 1 1. Thank you. you Thank you.

Ladies and gentlemen, and welcome to the Altalus Therapeutics Full Year 2022 Financial Results Conference Call and Fourth Quarter Operational Progress. As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Julia Wilson, Communications Consultant. Please go ahead.

Thank you, Norma. Good morning or good afternoon, everyone. And thank you for joining us to take part in today's call on the full year 2022 financial results and operational highlights for the fourth quarter 2022. I'm Julia Wilson, a communications consultant for Autolis. With me today are Dr. Christian Eytin, our Chief Executive Officer, and Dr. Lucinda Crabtree, our Chief Financial Officer. Before we begin, I would like to remind you that during today's call, we will make statements related to our business that are forward-looking under federal securities laws and the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These may include, but are not limited to, statements regarding the status of clinical trials and development timelines for our project candidates and our expectations regarding our cash runway. These statements are subject to a variety of risks and uncertainties that could cause actual results to differ materially from expectations and reflect our views only as of today. We assume no obligation to update any such forward-looking statements. For discussion of the material risks and uncertainties that could affect our actual results, please refer to the risks identified in today's press release and our SEC filings, both available on the Avesta section of our website. On slide three, you will see the agenda for today, which is as follows. Christian will provide an overview of our operational highlights for the fourth quarter of 2022. Lucinda will then discuss the company's full year financial results before Christian will conclude with upcoming milestones and any other concluding comments. Finally, we will, of course, welcome your questions. Over to you, Christian.

Thank you, Julia, and good morning to you all. Thank you for joining us. It's my pleasure to review our progress for the fourth quarter 2022. Moving to slide four, We're really pleased with our program and operational progress during the fourth quarter of 2022, which is highlighted over the next two slides. Firstly, we were delighted to announce in December that the pivotal phase two Felix clinical study evaluating OB cell in relapsed refractory adult ALL patients met its primary endpoint based on overall response rate in a preplanned interim analysis of 50 patients with morphological disease and has verified by an independent data monitoring committee. We're another step closer to bringing this potentially innovative treatment to an underserved ALL population, and I'll delve into the data in more detail later in this presentation. This positive data triggered a $35 million milestone from our partner, Blackstone Life Sciences, earlier than anticipated, and we're planning to provide a data update on all patients treated by mid this year, most likely at ASCO, with longer follow-up planned at the end of 2023, as well as planned DLA submission to the US FDA by the end of the year. December was a busy month for us. We also had a number of clinical updates at the American Society of Hematology annual conference, including presenting longer-term follow-up data from our adult ALL patients in the old CAR-19 phase one study of OV-cell, showing 35% of patients in ongoing remission at 36 months of follow-up median follow-up with no additional anti-leukemia therapy. In addition, OBCL continued to show high levels of clinical activity in relapsed refractory non-Hodgkin's lymphoma and chronic lymphoblastic leukemia patients, paired with a well-manageable safety profile. We were also very encouraged with the data we presented from our pediatric ALL program, the CAR-PAL Phase 1 trial of OTO-122, our dual-targeting CAR-T therapy targeting CD19 and CD22. with over 80% of patients achieving a molecular complete remission with no antigen-negative relapses observed. Additionally, we provided longer-term follow-up on the Libra T1 Phase 1 trial of Auto4 in peripheral T-cell lymphoma, with some patients experiencing durable metabolic CRs, including one patient up to the one-year mark post-treatment and, obviously, in continued remission. We will be providing updates on these programs over the course of this year, and we'll also be presenting data from the carousel study of OB-cell in peripheral CNS lymphoma patients, the McCarthy phase one trial of Auto-8 in multiple myeloma patients, and finally, the phase one trial of Auto-6-NG in neuroblastoma patients is expected to start in the next quarter. Turning to slide five, we've made some great operational progress during the quarter. Towards the end of the year, we closed a public offering raising aggregate gross proceeds of $164 million and net proceeds after underwriting discounts and offering expenses of $152.4 million, including a partial exercise of the green shoe by the underwriters. We believe we are now well-positioned financially to bring Ovisel, an innovative and potentially transformative treatment, to an underserved adult day-level patient population. In 2023, we will be fully focused on submitting a BLA application at the end of the year and working towards commercial launch in 2024. As I mentioned earlier, we also received a $35 million milestone from our partner, Blackstone Life Sciences, as a result of the positive interim analysis of OVCell in adult DLL. At the same time, we received an additional $35 million milestone from Blackstone as a result of planned activities supporting the performance and qualification of the OB-Cell manufacturing process. You will recall that we signed the agreement with Blackstone at the end of 2021, a part equity and part program financing collaboration for our lead candidate, OB-Cell, and we have now received $220 million of the total $250 million committed capital. We were very pleased to announce three deals, two in October 2022, and one post-period end in January 2023, which underscores what we believe is an industry-leading cell programming technology platform we have developed at Odalisq. We signed an agreement with Bristol-Myers Squibb, granting them access to our proprietary RQR8 rituximab-induced safety switch for incorporation into a set of selected cell therapy programs. In addition, Moderna exercised an option on one of the proprietary binders being developed against an undisclosed immuno-oncology target for the delivery of pioneering messenger RNA therapeutics. This license option stems from the deal we announced with Moderna in August 2021. Finally, in January 2023, we signed an agreement with Cavaletta Bio, which allows them to incorporate the RTRA safety switch into a cell therapy program for the treatment of autoimmune disease. The total license revenue was 6.2 million in 2022, and each of these deals have the potential for additional revenue in near-term option exercise fees, milestone payments, and royalties. We continue to make steady progress in our manufacturing and CMC operations. The first phase of the build of our commercial manufacturing facility was completed with the handover of the first of three clean rooms at the end of last year. We have named this facility the Nucleus, We're now working on the qualification and validation of the nucleus, and we remain on track for good manufacturing practice operations commencing in the second half of 2023. We're also undertaking the development work and report generation for the CMC package plan to support a BLA submission to the FDA. Finally, total cash and cash equivalent and restricted cash at the end of December were $382.8 million. With that, let's talk more about Ovisel, on slide number seven. OviCell has a unique mechanism of action. What's fundamentally different about our product candidate is that it has an ability to engage physiologically with the target cell, rapidly binding to the target, which delivers specificity, paired with a fast off-rate for rapid disengagement from the target cell once the kill has been delivered. This unique engagement drives maximal activity while minimizing toxicity And it's at the heart of the differentiated clinical profile we are observing in acute lymphoblastic leukemia, non-Hodgkin's lymphoma patients, and chronic lymphoblastic leukemia patients. Moving on to slide number eight. Our clinical experience with OB cell in ALL shows high overall response rate across all, sorry, population shows a high level of clinical activity across all indications. Our clinical experience with OV-cell in ALL shows a high overall response rate across all patient populations, including a very high level of clinical activity over the longer term that we have now observed in the All-Coron-19 study. We have a median follow-up of 36 months now in this study, and with a follow-up of 24 to 47 months of observation, we see that 35% of the patients are in long-term remission after receiving OV-cell and receiving no further antileukemia therapy. The safety profile is well manageable with low levels of high-grade CRS and ICANNs. The midsection of the slide shows the patients with long-term remissions and continued presence of CAR-T cells over the entire observation period. The program is developed under RMAT, PRIME, and ILAB designations. Moving to slide nine, we completed the enrollment and dosing of a pivotal study, a study we call the FELIX study in adult relapsed refractory ALL patients. And as I mentioned, we announced in December that we have had met the primary endpoint of overall response rate in an interim analysis based on the first 50 patients followed for at least three months of follow-up. Clinical benefit in ALL will be assessed based on patients remaining in sustained complete remission. We conducted this study in 34 centers, 24 centers in the US, seven centers in the UK, three centers in Spain during the peak of the pandemic. It is important to realize that relapsed refractory adult ALL patients are highly immune suppressed. and the pandemic poses a significant added risk to them. Moreover, due to access restrictions and various other pandemic rules and regulations, we could not access our clinical trial sites for the most part of the Felix study. You can imagine end-stage ALL patients are about as difficult a patient population to work with, particularly in an environment where there is a high risk of infection, and indeed, we did lose patients to COVID. In many ways, this study was more of a real-world study conducted under difficult circumstances. In addition to patient safety, every aspect of product delivery and logistics were pressure tested during this trial, with massively reduced air traffic and impact of the pandemic on our manufacturing teams. Remarkably, manufacturing for all patients from our facility in the UK turned out to be an asset also for US delivery. as the long-haul flights between the U.S. to the U.K. had priority over U.S. and also EU domestic flights. Next, key data readout is planned for ASCO in June this year. Moving to slide number 10. This slide summarizes the announcement we made in December regarding the pre-specified interim analysis of the first 50 out of 90 patients dosed that had reached at least three months of follow-up. The primary endpoint is based on overall remission rate, which includes patients in complete remission and patients in complete remission with incomplete bone marrow recovery, or CR and CRI. The ORR was 70%, and in fact, all recent programs in ALL have used ORR as the primary endpoint in the respective studies. Safety analysis was conducted on a larger 92-patient dataset and showed an excellent profile with high-grade cytokine release experienced in less than 3% of patients, and high-grade ICANNs or neurotoxicity in less than 8% of patients. ICANNs were fully reversible, and less than 25% of patients had any grade of neurotoxicity. In contrast, to approve T-cell or T-cell-engaging therapies, a very unusual safety profile in this population. As I mentioned earlier, this exciting data set triggered a $35 million milestone from Blackstone. Moving to slide number 11. This slide summarized our current experience with OB-Cell across ALL. As you can see, the data are highly consistent across the various studies, both in safety and efficacy. Worth noting is that the CAR-PAL and All-CAR-19 study were conducted prior to the pandemic, while both parts of the Felix study were conducted during the pandemic. Both the CAR-PAL and all CAR-19 study were conducted in the UK, while the FELIX study was largely conducted in the US. What we did pick up is that the patients in the FELIX study were more advanced in their disease based on tumor burden and increased presence of so-called extra-medullary disease. This is, in essence, a gain of function of the leukemia that allows it to leave the bone marrow and successfully settle and grow in other organs. Patients with extramedullary disease respond poorly to any type of antileukemia therapy. Moving to slide 12, to look further into the data we presented at ASH from the old CAR-19 study. When we then look into the outcome or long-term observation from the old CAR-19 study, we're up to, obviously, with four years of follow-up, and you can see that we have a quite unusual clinical profile. The clinical benefit in these patients is the ability to convert patients into complete remission and sustain them over long periods of time, which is obviously what we're seeing for a good proportion of these patients. When you look at the SWIM plot and moving from the bottom up, we had obviously some patients that did not respond to therapy. Then we have some patients that responded but relapsed quickly. The yellow circles are patients that relapsed with so-called CD90 negative disease. In essence, the leukemia became invisible to the therapy by losing the very structure the therapy was designed to recognize. If you then go a little further up, you see three red circles. Those are patients that relapsed because the CAR T cells, the OB cell product candidate, didn't persist long enough, and patients relapsed with CD19-positive disease. Above those, you then see a group of patients that are in long-term remission between two and four years without any additional therapy. Seven out of the 20 patients of 35% are in continued remission without receiving any additional antileukemia therapy with median follow-up of 36 months in the range of 24 to 47 months. Every single one of these patients has persisting CAR T cells. You see one additional patient with long-term remission who received a stem cell transplant while in complete remission. Moving to slide 13. Blincyto, a T-cell-engaging CD19-targeting monoclonal bispecific antibody, has become the standard of care in relapsed refractory adult ALL over the last few years. Key to its success has been the well-manageable safety profile. Key focus from a patient management perspective is the monitoring of neurotoxicity, or ICANs, which impact 65% of patients treated with Blincyto. In contrast, Obicel had less than 25% of patients experience ICANs of any grade. High-grade CRS for Blinzaito is low, with about 5%, and Obicel seems to be similar and potentially slightly better in terms of high-grade CRS. In contrast to Blinzaito, Decardus, a CAR-T program approved for this indication, induces high-grade cytokine release syndrome in 26% of patients, and high-grade neurotoxicity in 35% of patients, while 87% experience neurotoxicity of any grade. 40% of patients receive vasopressors. Managing such a safety profile often requires access to ICUs. Finally, inotuzumab, while active, is primarily used as a bridging therapy. Moving to slide 14. The market opportunity in relapsed refractory ALL is, in fact, unchanged, with about 3,000 patients in high need for therapy between the U.S., Europe, and Japan. Moving to slide 15, Blincyto, the standard of care in relapsed refractory ALL, has reached sales in 2022 of $583 million, with a year-over-year growth of 24%. This product is commercialized by Amgen. Currently, the product reaches about 2,000-plus adult patients with ALL, on average receiving two cycles of Plincyto. Patients with low disease burden can receive up to four cycles of Plincyto at a combined cost comparable to CAR T therapy. Key to Plincyto's market penetration is its well-manageable safety profile, which allows delivery in non-academic hospitals in addition to the academic centers. We believe that OBSEL with its high level of clinical activity, attractive safety profile, and one-time administration is well positioned to capture that opportunity. When we look overall in terms of the price level for CAR T therapies in ALL, they are in the range of $450,000 in the US. Moving to slide 16. When we look at the steps forward, first of all, we're planning to disclose the Felix data from all patients' dose in the mid-2023, likely at ASCO and also at EHA. Long-term follow-up is planned for ASH. We're targeting the BLA submission for the program towards the end of the year, MAA filing towards the end of the first quarter of 2024, and the UK filing in the second quarter of 2024. That sets us up very nicely for the key territories that we expect to be initially active in. In addition to the mature clinical data, The submission will also require data from the validation of our commercial manufacturing site. This work has been a key focus throughout the first half of 2023 and will continue into the third quarter. Importantly, our commercial manufacturing facility is set up to cover supply for approximately two-thirds of the estimated market from the start. As we're moving through 2023, we need to prepare three key areas for commercialization. creating awareness for the program through a focused medical affairs program. Second, establish the value proposition for payers in our HTA doses. And finally, third, prepare for and start center onboarding, a process that will take between nine and 15 months to get each center ready to deliver CAR T therapy. Moving to slide 18, to talk about the broader opportunity that we see with OB-SELF. As part of the OLCAR19 extension study, we have been evaluating OBCEL in relapsed refractory non-Hodgkin's lymphoma and chronic lymphoblastic leukemia patients. We see consistently very high response rates combined with a very attractive safety profile suitable for outpatient use. The data will form the basis for the selection of a second indication after ALL. In terms of the life cycle, we started to work on the next version of OBCEL, which we call OTO1-22. We're looking to minimize with this product CD19 antigen loss-driven relapses with its dual targeting approach. Building an OB cell, we're adding a highly potent CD22 car that can recognize very low amounts of CD22 on the surface of leukemia cells. This program was initially evaluated in children who had failed Kimraya or were not eligible for Kimraya therapy. In this very challenging patient population, we saw an 83% molecular response rate, and none of the children relapsed with de novo CD19-negative disease. Comparing this activity to Obicel, we would have expected a molecular CR rate of approximately 40, maybe 50%. We're working on further streamlining the manufacturing process for Auto-122, knowing that we have an attractive lifecycle option. Timing of investment decisions in Auto-122 will be balanced with additional indication investments for Obicel. Slide 19. Switching gears, moving on, switching gears to slide 20, as well as 21. Our technology platform allows us to engineer a range of properties into T cells to drive specificity of recognition, resilience against negative signals used by tumor cells to evade T cell attack, and providing survival signals for T cells. Our strength in T cell engineering drives our pipelines. and is also at the heart of the three collaborations reported on in 2022 and early 2023 with Moderna, BMS, and Cavaletta. On slide 22, we have a quick summary of the earlier stage programs in T-cell lymphoma with Auto 4-5, Auto 6-NG in neuroblastoma, and Auto 8 in multiple myeloma. Both Auto 4 and Auto 8 are in phase one clinical studies, and Auto 6-NG is expected to start phase one in the next quarter. Moving to slide 23. T-cell lymphoma has a very high medical need, quite similar to BALL. In fact, when you look at the NCCN guidelines, it basically says that once you're through the frontline therapy and fail, you have to go on a clinical trial. Moving to slide 24. With its unique targeting approach, Auto4 starts to show meaningful clinical impact at the higher dose levels that we have evaluated. The first metabolic CRs are reaching one year post-treatment, and we continue to follow those patients. In addition, we have streamlined the manufacturing process and are exploring the activity in an additional cohort, and we're planning to report on that outcome later in 2023. Moving to slide 26 to talk about manufacturing. Cell manufacturing is at the core of any autologous cell therapy, developing a highly reliable, robust, and economical process is critical for the success of any program. In addition, we have to be able to deliver product at scale and matching the capacity to the size of the medical need in its indication, and it is important to be able to do that to have a successful rollout of your therapy. Building on the robust and well-corrected process used to manufacture for the Felix clinical study, We're standing up our commercial cell manufacturing facility called the Nucleus about a mile away from the clinical trial manufacturing site we had used for the study. This proximity is important as we'll be able to move our entire staff to the new facility, and in fact, many of them are already in the process of validating the Nucleus facility. The capacity of the Nucleus in its initial setup is 2,000 patients per batches per year, or about two-thirds of the adult ALL market size in terms of capacity. The nucleus has been a fantastic project to realize with an innovative design and about 75% off-site building to accelerate the build while maximizing the quality of the build. So with that, I would like to turn to slide 28 and pass the call over to Lucinda for our fiscal year 2022 financial update. Lucy?

Thanks, Christian. Good morning or good afternoon to everyone. It's my pleasure to review our financial results for the fiscal year to December 31st, 2022. Cash and cash equivalents and restricted cash at December 31st, 2022 totaled $382.8 million, as compared to $310.7 million at December 31st, 2021. Net total operating expenses for the 12 months ended December 31st, 2022 were $168 million, net of grant income and licence revenue of $6.4 million. as compared to total operating expenses of $165 million, net of grant income and licence revenue of $2.3 million for the same period in 2021. Research and development expenses increased by $7.2 million to $142 million for the year ended December 31st, 2022, from $134.8 million for the year ended December 31st, 2021. This was primarily due to the following. An increase of $11.6 million in clinical costs and manufacturing costs, primarily relating to our O2Cell clinical product candidates. An increase of $0.4 million in legal fees and professional consulting fees in relation to our R&D activities. An increase of $0.2 million related to information technology infrastructure and support for information systems related to the conduct of clinical trials and manufacturing operations. an increase of $0.2 million in cell logistics costs, a decrease of $3.7 million in facilities costs related to the termination and closure of our US manufacturing facility in 2021 and a shift in our overall manufacturing strategy, a decrease of $0.9 million in depreciation and amortization related to property and equipment and intangible assets, and finally, a decrease of $0.6 million in salaries and other employment costs, including share-based compensation expenses, which is mainly due to lower exchange rates used upon consolidation for the year ended December 31st, 2022, compared to the year ended 31st, 2021. And this was offset by an increase in employees engaged in R&D activities. General and administrative expenses remain consistent at $31.9 million for the year ended December 31st, 2022 and 2021, respectively, primarily due to the following. An increase of $1.4 million in salaries and other employment costs, including share-based compensation expenses, mainly driven by an increase in the average number of employees engaged in G&A activities. An increase of $0.3 million, primarily related to information technology costs. A net increase of $0.1 million in legal fees and professional consulting fees in relation to our G&A activities, which was offset against lower D&O insurance, director and officer insurance. a decrease of $1 million of commercial preparation costs due to the timing of related activities, a decrease of $0.4 million in facilities costs related to the termination of certain lease agreements in the prior year, and a decrease of $0.4 million in depreciation and amortization related to property and equipment and intangible assets. Interest income increased to $1.7 million for the year ended December 31st, 2022, compared to $0.3 million for the year ended December 31st, 2021. The increase in interest income of $1.4 million primarily relates to the increase in interest rates on our interest-bearing bank accounts and short-term investments during the year ended December 31st, 2022 compared to 2021. Interest expense increased to $8.9 million for the year ended December 31st, 2022 as compared to interest expense of $1.1 million for the year ended December 31st, 2021. Interest expense is primarily related to the liability for future royalties and sales milestones, which arose upon the execution of our strategic collaboration and financing agreement with Blackstone in November 2021. The increase in interest expense for the year ended December 31st, 2022 is primarily driven by the full year of the liability related to the Blackstone collaboration in 2022 compared to a partial year liability accrued in 2021. Other income or expense increased to an income of $2 million for the year ended December 31st, 2022 from an expense of $1 million for the year ended December 31st, 2021. During the year ended December 31st, 2022, we recognised a foreign exchange gain of $1.7 million, a sublease income of $0.2 million, another income of $0.1 million. This compares to an expense of $0.1 million as I mentioned for the year ended December 31st 2021 which included a foreign exchange loss of $2.2 million offset by a gain on lease terminations of $2 million and other income of $0.1 million. Income tax benefit increased to $24.4 million for the year ended December 31st 2022 from $23.9 million for the preceding year ended December 31st, 2021, due to an increase in qualifying research and development expenditures for the period. Net loss attributable to ordinary shareholders was $148.8 million for the 12 months ended December 31st, 2022, and this compares to $142.1 million for the same period in 2021. The basic and diluted net loss for ordinary share for the 12 months ended December 31st, totaled $1.57, compared to a basic and diluted net loss for ordinary share of $1.97 for the 12 months ended December 31st, 2021. Finally, Autolis estimates that its current cash and cash equivalents on hand and anticipated project financing payments from Blackstone will extend the company's runway into 2025. And now back to Christian to give you a brief outlook on expected milestones. Christian.

Thanks, Lucy. Moving to slide 30. Finally, we think we have an exciting year ahead of us. Key focus is on getting OBCEL into the regulatory process with BLA filing targeted towards the end of the year, followed by filings in Europe in the first half of next year. Next up are the planned Felix data presentations mid-year 2023. In addition, we're preparing for commercial product supply and launch readiness. Finally, we also expect to provide updates on the pipeline programs with additional data and follow-up during the year And with our key programs unpartnered at this stage, we have opportunity for setting up collaborations. Moving to slide 31. So with that, we believe we're at a very interesting point with the company. We've got the cash to deliver a very significant value step. We got the data to show that with OBSEL, we have a differentiated product profile that addresses the high medical need with limited competition and with possibly a transformational outcome. Alongside that, we have additional opportunities for overselling broader indications and a valuable pipeline of other oncology programs. As I mentioned, we're excited about our manufacturing facility, and we have a strong technology foundation validated by our collaborators, BMS, Moderna, Cavaletta, and we look to do more deals of that nature in the future. With that, thank you very much, and we're happy to take questions.

Thank you. To ask a question, you'll need to press star 11 on your telephone. To withdraw your question, please press star 11 again. Please wait for your name to be announced. Please stand by while we compile the Q&A roster. One moment for our first question. Our first question comes from the line of Gil Bloom with Needham & Company. Your line is now open.

Good morning and good afternoon, and thanks for taking our questions. Just the first one on the data that was published from the FELIX study. So, there appear to be a slightly higher incidence of grade 3 CRS in ICANs than kind of earlier studies. Now, given that autolysis goal is to have oversell administered in the community setting, how do you think physicians will adjust to levels of high-grade AEs?

Gil, first of all, thanks a lot for joining. Really good question. So I think it's important when we put the data in perspective. What we did show is that we have less than 3% high-grade CRS and we have less than 8% ICANNs. This is a level of grade three events for both types of adverse events. That is at or below the level of purple in cycle, which is currently used in non-academic centers. And so we believe that actually the profile is very well suited and matches the experience actually already established with the standard of care in those centers. So we believe the data is very well suited and supportive of that broader use of the product.

Yeah, that's very helpful. And another question about the filing. So what data do you expect to include in your BLA? I mean, you're going to have additional data by the filing date, including ORR and the duration of response, but will you also be including data from your MRD positive cohort?

So, really good question. So, first of all, in terms of our, you know, of demonstrated clinical benefits in the morphological cohort, which are patients that have more than 5% disease burden at the time of inclusion into the study, the focus is to demonstrate that it can actually convert these patients into complete remissions that are sustained over time. So what you will have to look at is CRs with a minimal level of follow-up to actually establish, in fact, an appropriate level of clinical benefit. So time-dependent outcomes are absolutely a critical parameter that will have to go into a BLA and will be at the core of the assessment of clinical benefit for the product. Second, of course, the safety profile was then a key part of the assessment to understand actually the benefit-risk ratio that you have with the product, which is obviously a very key parameter to understand the suitability of a product in any given indication. With regards to the focus, when you think about the review, it really will be focused initially on the patients that have morphological disease. We obviously have also assessed mineral residual disease in these patients, the level of MRD signals that we have in the patients, et cetera. But the inclusion criteria are patients with morphological disease. The work that we do to expand the knowledge of the properties of the product across the entirety of disease burden, which includes, as you pointed out, also patients with mineral residual disease, is a data set that obviously is being generated, but it is also a data set that is not going to be part of the initial filing in terms of, it will go into safety, but it is not an aspect of the efficacy evaluation for the initial filing that we're planning.

Thank you for the clarification. And last one from us, you did mention that from your scientific collaborator, there may be some data on multiple myeloma. What do you think the gating factor would be for further development of that program, given how crowded the market is? Thank you.

Yeah, very good question. So what you're referring to is the AutoAid program that we're working on with our colleagues on the academic side. We're currently running a phase one clinical trial to evaluate the activity of AutoAid in relapsed refractory multiple myeloma patients. I think we're at an interesting spot with regards to the CAR T therapies in multiple myeloma. We have obviously seen very nice levels of activity with the two approved products in the space, but there is also a very high unmet need and at this point still a remarkable inability to meet the demand in this indication, and it is likely going to continue for quite some time. So with regards to what we're looking to see with the program, we also want to see a very high level of complete remissions in these patients combined with deep molecular remissions. And at the same time, obviously, we're looking at the safety profile. We clearly want to see a very significant level of clinical activity in these patients as a basis to consider taking the program forward. And if we're at that point, you know, clearly would anticipate that this would make sense to do in a partnership.

Okay. Thank you, Gil.

Thank you. One moment for our next question. Our next question comes from the line of Mara Goldstein with Mizuho Group.

Your line is open.

Great. Thanks so much for taking the questions. First of all, on the multiple myeloma data that you do anticipate having this year, can you just give us some element of just the scope of that number of patients and what exactly we should be prepared to be looking at? And then I also wanted to ask on ObaCell and thinking forward from a competitive perspective, Is a competitive go-to-market strategy, you know, versus Blinzaito or Tocardis? Can you help us understand how you plan to position Obacel?

Yep. Hi, Myra. Thanks a lot for the two questions. So the first question was related to the AutoAID study. The AutoAID study is a small phase one clinical study, so we're looking at around 10 patients. as sort of the initial experience, and then we'll take it from there. So it's going to be initial look at the profile of the product in that initial set of patients. Now, with regards to Obicel, what we're expecting to go for is obviously a positioning of the product in the relapsed refractory setting, whether patients have had already received Blinzide or are post-Blinzide dome. And I think that is sort of obviously what the current study actually is evaluating. It's patients that are in very advanced disease and with a portion having had Blenzyte or in etuzumab or in a portion who didn't. So you're looking to position the product both in parallel or after Blenzyte therapy. Obviously, the Ticardis obviously is positioned in that exact same way, so it would be the same type of positioning that we would expect for the program.

Okay, thank you.

Thanks, Mara.

Thank you.

One moment for our next question.

Our next question comes from the line of Matthew Phipps with William Blair. Your line is now open.

Hi, Gretchen. Thanks for taking my question. At the recent European CAR-T meeting, Kite or Gilead presented some long-term follow-up from Zuma 3 with Tecardis. And, you know, it shows very few patients really remaining in CR even beyond two years. And so it's a pretty big contrast to the data you presented at ASH from a follow-up with Alcar-19. It shows, I don't know, 35%, 40% of patients still in CR at three years. So do you expect the Felix data to recapitulate the Alcar-19 durability, given you've talked about a little bit tougher to treat patient populations with extramodular disease and such? And I guess just how do you kind of get that durability message across to physicians in your kind of education process?

So really good question. Thanks for joining, Matt. It's really what you're pointing to is really kind of the, I think what we believe was really remarkable data from our initial evaluation of OV-cell in this patient group. And obviously, as you pointed out, what we did see is a stabilization of our long-term durability curves, et cetera, with, you know, patients staying in sustained remissions about, as you pointed out, by 35% of the patients being in that category. So that is a remarkable outcome, and it's clearly something that, you know, has not been possible when I developed with my old team, and has not been shown, clearly not been shown for the carcass either. So what we're looking, what we're expecting to see with, oh, we said also the Felix study is that we also see a similar shape of the curve, where exactly that stabilization will ultimately occur. I think that's too early to tell. We don't have enough follow-up in the study at this point in time. But that is what we're looking for, and that's what we expect to see. Whether it's going to be the exact same level or a slightly different level, we do not know at this point in time. And as you pointed out, obviously one of the things that we do have um had in terms of inclusion into the studies obviously patients that certainly in that you know initial data set that we presented that had you know pretty significant uh levels of uh disease burden as well as extramedullary disease which frankly was not too much a surprise given that that first 50 patient data set really was truly peak pandemic um and so you know we'll see obviously what the full data set looks like but you know we're obviously expecting to see the same shape of the curve. And at this point in time, we can't exactly say where that's actually going to come out. That requires long-term follow-up. The fact that we saw the persistence data track what we had seen before, I think, is very encouraging because, obviously, that was a clear correlation that we did see that all these patients that had long-term outcomes also had long-term persisting CAR T-cells. And the shape, when you look at persistence coming out from the trial, as we had indicated from the interim analysis, was tracking the all-car persistence curve. So that is encouraging. I think it's sort of the lead indicator, but obviously requires long follow-up to sort of be clear about where exactly we might be landing.

Okay. Can I also ask, what At what point do you request a pre-BLA meeting this year? Is that something you do after kind of the ASCO update?

So it's a really good question. So I think what you want to do at the time you go for a pre-BLA meeting is you want to actually have, you know, the data with sufficient level of follow-up so you have a very clear positioning around the outcome that it can actually present and discuss with the agency. And obviously the data we're gonna go with into ASCO, I think will start to give us, I think, a good level of observation.

So we would expect that this is going to be an interaction post-ASCO.

Okay, good, thanks, Christian. Okay, thanks a lot, Matt.

Thank you, one moment for our next question. Our next question comes from Kelly Shi with Jefferies. Your line is now open.

Congrats on the progress, and thank you for taking my question. Regarding the baseline for patients enrolled in Alex trials, does it appear consistent with phase 1B cohort under a fraction of patients with greater than 20% of bone marrow blasts? And also, will we be able to provide more information to such as patients with the CNS disease and the actual medullary disease presence on the PHYLEX trial. Thank you. I also have a follow-up.

Okay, so thanks for joining, Kelly. Nice to have you on the call. First of all, in terms of the patient population, overall, obviously, the patient population is close and very close to what we've been seeing in the phase one portion of the study. And What we also expect to see is obviously some variability as we're sort of going through the peak pandemic in the study as well. So we're close. We may actually have seen even a bit of a worsening after that. And if you look at the ORR, obviously small numbers, but it went from 75 to 70%, which could be indicative of a slightly worse population. So that is sort of, I think, where we are. We'll obviously gonna present that in detail, the underlying patient characteristics, et cetera, at the full data presentation. It's going to be also an important piece of information, I think, will help to put the data into the appropriate level of perspective as well. So that's sort of the answer to the first question.

What was the second question?

Thank you. Super helpful. So my second question is, given the differentiated profile, especially on safety front of auto ones, Would you consider exploring the opportunity in autoimmune indications, such as lupus, given that some proof of concept data has been available?

Thanks. Thanks for the question. Well, what you're pointing to is a really remarkable data set that was developed by Andreas Mackensen and his team at the University of Erlangen. who've done a fantastic job evaluating the utility of a CD19 CAR-T approach in patients with refractory systemic lupus. The outcome of the data was quite remarkable. It's an ancient medicine paper published at the end of last year. We know the team actually had also worked with the team at the early stages of incited development, so way back, almost 20 years back. Really good data set. We believe, obviously, that, you know, Obicel has a remarkable profile, obviously, now with a lot of data around the safety of the program and clearly has an absolute outstanding safety profile, which is important when you think about use in autoimmune disease. And the other aspect, of course, is that, as we all learned in this space, is the fundamental tricky part in this with autologous CAR-T therapies is you actually have to have an ability to manufacture at scale and do that at quality and economically. And obviously that's one of the key things we have been developing for OpiCell for its initial application in ALL. So absolutely we're following that field very closely. We think it is a very attractive potential future use of programs that are very safe and very active and we believe Obicel fits that very well.

Thank you. Thank you. Thank you.

And our next question comes from the line of James Shin with Wells Fargo. Your line is open.

Good morning and afternoon, guys. Just a couple from our end. I just want to dig a little deeper into the positioning of Obicel. So do you envision Obacill could be positioned ahead of Blincyto at some point? And is there a future study exploring this? And then on a related matter, I mean, cell therapy as a whole has started to make good headway to the earlier with a couple oncologists. Seems there's some regulatory hurdles, namely the FACT immune effector cell accreditation that makes cell therapy entering the community setting a little bit difficult or intensive. Any thoughts there? Really appreciate it.

Yeah, well, first of all, thanks for joining, James, and I think, you know, a very interesting question. So, first of all, in terms of sequencing, you know, at this point in time, obviously, Blincyto is approved both in the relaxor factory setting as well as also in patients that have mineral residual disease and that are basically in CR1 or later. So in essence, it's patients that have gone through frontline therapy with still remaining residual disease. They're technically in complete remission, but they still have measurable leukemia cells at low levels, hence minimal residual disease. And so the product obviously has labels in those two settings and obviously has been evaluated now as part of the frontline therapy. So in that sense, Blinzaito will have a place in this earlier part of the treatment scheme, and we expect it to just sort of move up into that earlier setting. Now, what we see from the Dicardus approval is that Dicardus was approved for relapsed refractory patients without actually defining, you know, is this a second, a third line, or a fourth line. Actually, it's any relapsed refractory setting. And so, we would expect that the OB cell would have the same type of scope initially. And obviously, with the work we do on minimal residual disease and evaluating the activity of the program there, I think should allow us to eventually position the program similar to the way that when Zyko is positioned. But that obviously takes time to sort of actually move up in terms of the lines of therapy. So I think that's the first part of the question. The second part of the question was more around how do you actually position CAR T therapy outside of the academic centers considering that you need a level of training or accreditation of those centers to be able to actually deliver the product. And I think what we need to understand is that particularly with OVCell, we do obviously have a very, very similar profile to incite them. In fact, in patients with low disease burden, obviously, we do have an even better profile that we've shown in these end-stage high tumor burden patients that we obviously quoted in our interim analysis. So when you look at that population that has particularly lower disease burden, but even the one that we have treated now, the adverse event profile that we have in these patients is exactly what the physicians today do manage with Blinzaito. The same level of higher-grade CRS. In fact, it's a little less than what Blinzaito has, and it's actually less neurotoxicity than what you see with Blinzaito. What's very important in that context is that, obviously, when you look at the overall level of neurotoxicity, it's in about two-thirds of the patients have some level of neurotoxicity with Blenzyto, which requires you to monitor the patient, to observe them, et cetera, make sure that you stay on top of it. What we have with OV-cell in a more advanced patient population, because obviously we include Blinzaito failures in the FELIX study, we actually have a little more than 20% of patients that have some form of neurotoxicity, so it's actually substantially less. So the actual monitoring level is less than burden that we have, and with that, we believe there's an opportunity to actually manage this, and with the experience on Blinzaito, should be able to manage this. in non-academic hospitals and associated potentially outpatient settings down the line. But that is sort of where that is. Now, in terms of the ability to deliver CAR T therapy, there's obviously a level of not only patient management that's required, which obviously is covered very well with the experience of lymph cycle, but it is also obviously requires you to actually handle the cells, and manage the cells as part of the therapeutic approach. And that requires a level of training that obviously needs to be put in place. And we believe that that is a possibility for non-academic hospitals. And then we have to see how further out you might actually be able to go. But I think this gives you a very good penetration and ability to reach the ALL population with this profile, as we see basically demonstrated through the insights already.

Thank you.

Thank you. One moment.

And our next question comes from the line of Sebastian Van Schoot with Van and Scott Kemper. Your line is open.

Hi, good morning and good afternoon, everyone. It's Sebastian van der Schoot from Landshut Kempen. No worries. Congrats on the projects. I was just wondering for the opportunity of OB cell and other indications beyond AOL, will there be additional updates on the all-car study for the other indications with additional patients? And are there any of these indications that you believe would allow for an accelerated approval pathway after additional data can show the same level of efficacy as this goes as last year? And then you also spoke a little bit about the lifecycle management with auto-122. Can you expand on your thinking on the possibility to continue development of auto-122 beyond the pediatric indication into adult hematologic indications? Thank you.

Thanks, Sebastian. Thanks for joining. So when we look at the opportunity that we see with OBSEL, obviously what the product is, you know, has a remarkable profile is to basically remove the B-cell compartment, both on malignant cells as well as healthy cells, and do that with a very good safety profile. So that's the basic property of the product. Where that is suitable, obviously, is in leukemias. It is in non-Hodgkin's lymphoma, which is what we're evaluating, and CLL, what we're evaluating as part of the old CAR9T study. And then, as Kelly was pointing out, there's also certain applications in the autoimmune space where that might become quite interesting, and some delete data would indicate that you might even be transformational in those settings. So this is sort of the range I think you have in terms of opportunity, significant while on the oncology side, but also one that starts to build up also in the autoimmune side. So that's the range. And now the question of choice. What we're seeing in our old CAR-19 study is really that we're having a very high level of clinical activity across the entire range of these indications. And that gives us a lot of confidence in terms of the overall quality of the product. In terms of the individual indications, obviously, you have opportunities looking at that. DLDCL is an example where we see very high levels of complete remissions that are sustained. We haven't seen any relapses today in that cohort, which is quite remarkable. There are also obviously very interesting data in mantle cell as well as in C-level that we have seen. Now, all those indications are opportunities to develop in segments of the indication, which allows you to move relatively quickly and with an accelerated path. And then depending on the indication you look at, you also may then want to, as you sort of go for a last line setting, will want to actually start looking at an earlier line study as well, which then typically would be a randomized control study in that earlier line, and would want to move on that reasonably, in a reasonable sort of time relation to your last line setting. So that's sort of the opportunity, and we're looking at these, and also the data from the old CAR data, old car study does give us, I think, a very nice basis to sort of, you know, develop the right options for the investment. You then also asked about how, in that conversation, how Auto 122 fits. And as we indicated, we obviously do know now with Auto 122 that we have a very active program. It appears to do exactly what we want in terms of avoiding the occurrence of target negative relapses, which is the key thing that obviously you'd be looking to address. And where we know that it's particularly important is obviously in acute leukemia. There's been initially reports that there is a certain proportion of patients that do actually show CD19 negative relapses in the context of diffuse large B-cell lymphoma. There haven't been as many reports more recently. In our own hands and with OB-cells, we haven't seen CD19 negative relapses, nor did we with our planner program. So whether or not that is a major issue to actually address in those indications, I think is unclear at this point in time. And I think that is sort of one of the questions I think we'll look into in terms of the ability to broaden the utility of the dual targeting approach into additional indications. But where it's very clear is that in ALL, that is certainly a driver for relapse, both for children as well as for adult patients. And we believe at some point it makes sense to consider that program to move into the succession of OPCL in the acute leukemia setting as well. So that's sort of, I think, in terms of the range as well as the way we're thinking about it. And ultimately, it's a set of investment decisions, and it's a question of sequencing those investments. And I think the priority will first be on actually broadening the opportunity for OBSEL, and then in a second step, actually then moving forward with O2-122 in terms of the actual life cycle to OBSEL.

Great. Thank you very much. Thanks, Sebastian.

Thank you. One moment.

And one moment. Our last question comes from . Your line is open.

Hi, this is Karina for Astica. Just have a few questions on pricing. With the filing due by year-end, how are you guys thinking to price Obicel? And can you also discuss some preliminary feedback you have received from payers in the U.S. and Europe? And also, is there any potential for your pricing power change with detailed data at ASCO? Thank you.

Sorry, Karina, I didn't get the last part of the question.

The pricing power with the next update at ASCO.

Oh, I see. Okay. Thank you. Well, first of all, thanks for joining, Karina. Interesting questions related to pricing. I think what we've been seeing across the states is two dimensions. First of all, we're having in NLL specifically, obviously with BlinCycle and the use of BlinCycle in patients with lower disease burden, we also do see a use of up to four cycles in those patients, which, you know, is basically getting the price for that product into the range of between $400,000 and $500,000 per patient in the US. So that's sort of one benchmark, which is standard of care and kind of what bracket that is. When you then look on the approved CAR T therapy in ALL, that is in the range of $450,000 during the course they're expected to be during the course of this year. So that's sort of the second sort of I think, a bracket that we're seeing in the U.S. And we would expect that we would be pricing in a similar range. Obviously, we believe that we do have a product that actually allows you to be more efficient from a cost perspective because the product should induce less toxicity, require less patient management. And with that, I think there should be a good health economic argument supporting the use of Obicel in addition to, obviously, its clinical pro. With regards to Europe, we're also seeing across the board with CAR-T therapies that the prices are sort of starting in the range of where the U.S. prices are with some level of discount depending on the jurisdictions you're looking at and the indication that the products are delivered in. So that is more variable, and we'll see how that also develops over the upcoming period of time. And so we'll obviously keep you updated how that field evolves over time, but I think this is where it stands and the current expectations is that we would consider to be somewhere in line with what we've been seeing in the space. In terms of data flow, I think we're going to have a very interesting data flow as we go through this year. Obviously, at ASCO, obviously data from all the patients that were dosed, but also still a limited follow-up on some of the patients that I think are focused on a lot of their descriptions of the patients, the basic activity, the behavior of the product in every aspect. And then I think as we go to ASH and then even later into 2024, I think obviously much more longer-term follow-up, which I think will flow obviously as an important parameter into the HTA assessments and value assessments that will be conducted by the payers.

So that's kind of where we are with those.

So just, do you think the longer-term follow-up is going to push pricing higher?

Well, first of all, the impact of the longer-term follow-up and showing an impact on longer-term follow-up, I think, is obviously strengthening your value argument for the product. So I think it will clearly make a very strong case for using the product based on more patients achieving long-term outcome. And I think that is certainly going to be a key parameter that will drive the value assessment by anyone who would look at the program. So it will definitely influence the overall assessment. To what extent that would influence pricing, I think it's premature to discuss.

Okay, thank you.

Thank you, Karina.

Thank you. At this time, I'd like to turn the call back over to Mr. Christian Eaton for closing remarks.

Well, first of all, thanks, everybody, for joining. Obviously, it was great to be able to update you on a very exciting fourth quarter that we're running through. We're in, I think, a very important stretch as we go through the course of this year, getting the product ready for filings, and I think, obviously, a real opportunity for substantive data updates as we go through the course of the year with the next ones, obviously, expected for the Meteor section. So really looking forward to meeting you, hopefully in person, and updating you on the program along those venues and wishing you a successful first half of the year. And then I think for all of us, I think a more relaxed second half of the year with some hope that some of the big picture items hopefully will start to turn into a more favorable environment. So with that, I'd like to thank you all and wish you a good day.

Ladies and gentlemen, thank you for your participation. And due to time limitation, we were conscious of the time and we weren't able to reach out to everyone. So management will connect with everyone that weren't able to connect to the call after the call. Thank you very much. Please enjoy your day. You may now disconnect.