Autolus Therapeutics plc (AUTL) Earnings Call Transcript & Summary

Good afternoon, Good morning, and welcome to Autolus' Capital Markets Day. Thank you for joining us today. I'm Alexandra Deschner, Investor Relations Consultant for Autolus. I'm joined today by Dr. Christian Itin, Chief Executive Officer, together with members of the management team and esteemed key opinion leaders. We will be taking questions during today's webcast. If you would like to ask a question, you can do so in writing via the webcast page using the Ask a Question button. Before we begin, I would like to remind you that during today's webcast, 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 time lines 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. On Slide 5, you will see the agenda for today. I will now hand over to Christian for opening remarks. Over to you, Christian.

Good morning, and good afternoon, ladies and gentlemen. I would like to welcome you to our Capital Markets Day event. We have a great program for you today, focused on acute lymphoblastic leukemia. Next slide, and one more. We will start our presentation today with Professor Lori Muffly from Stanford University, reviewing the disease, therapeutic options and medical need for adult patients with ALL. Professor Claire Roddie from UCL will introduce you then to obe-cel and the initial clinical experience in patients with ALL. Following Dr. Roddie's presentation, we will hear from one of her patients on her experiences living with an ALL diagnosis. With this deepened understanding of the physician and patients view of this challenging disease, we will switch gears and look with Dr. Matthew Gitlin at the ALL market and the prospective payers are taking. Finally, Chris Vann, our Chief Operating Officer at Autolus will lead you through the commercial road map for obe-cel before we conclude with a Q&A session. Now I would like to introduce you to our first speaker, Professor Lori Muffly. Next slide. Dr. Muffly is Associate Professor at the Department of Medicine, Blood and Marrow Transplantation and Cellular Therapy at Stanford University. She's held a number of academic posts at Stanford's Department of Blood and Marrow Transplantation and Cellular therapy. Dr. Muffly trained at the City Chemo Medical College, Thomas Jefferson University in Pennsylvania, did a residency at Dartmouth Hitchcock Medical Center in New Hampshire, followed by senior fellowships at University of Chicago Hospitals and Colorado Blood Cancer Institute in Denver, specializing leukemia, lymphoma and stem cell transplantation. Since 2014, she teaches at Stanford Medical School. Dr. Muffly is a clinical fellow in blood and marrow transplantation and the staff physician in cancer and cell therapy and blood marrow transplant at Stanford University. Dr. Muffly is also a member of the Center of Cancer Cell Therapies at Stanford, the American Society of Clinical Oncology, the American Society of Hematology and the American Society for Transplantation and Cellular therapy, which is a board certified in hematology and medical oncology and has been a principal investigator for a number of cell therapy and leukemia clinical trials and has published and reviewed papers in dozens of peer-reviewed journals. With that, I would like to hand over to Dr. Muffly. Lori, over to you.

Thank you so much, Christian, for that introduction. It's an absolute pleasure to be here with you this morning on West Coast U.S., so at 7:00. But I get to talk about my favorite topic, which is acute lymphoblastic leukemia. Next slide, please. So for those of you on the call, you probably already know that acute leukemia is a very aggressive malignancy that evolves rapidly. And so this figure here shows essentially how we think about acute leukemia currently, which is that a population of stem cells within the bone marrow environment undergoes transformation and becomes leukemic prone stem cells and then either due to acquisition of mutations or due to some change in the immune or microenvironment, T cells then become either acute lymphoblastic leukemia or acute myeloid leukemia. Today, of course, we're focused on acute lymphoblastic leukemia. This is the most common cancer in children, but approximately 50% of ALL cases are in adults. And this preferentially, this disease preferentially affects young adults between the ages of 18 and 40, which is a really important population in cancer medicine. There's 2 large groups of ALL. B cell ALL accounts for approximately 85% of pieces, whereas T cell ALL is much more rare. And today, we will be focusing on acute lymphoblastic leukemia in adults, B cell subtype. Next slide, please. So this is a very challenging disease. I am a clinician and clinical investigator, and this is the disease I focus on, obviously. And I will say, despite recent advances that we'll go through briefly, it still remains a very, very difficult disease to treat and cure. The majority of adult patients who receive a diagnosis of B cell ALL will relapse even after initial response. The overall outcomes in ALL in adults still are hedging around 40% to 50% survival rates. And once patients relapse, their outcomes remain poor with median overall survival of less than a year. There are new therapeutics we're going to go through in the next slide that are very exciting. And thus, we do see improvements over the last 5 to 10 years, but there remains a substantial unmet need for patients with relapsed/refractory and high-risk B cell ALL. Next slide, please. So what has changed recently? And so the figure on the right represents the NCCN guidelines for the treatment of relapsed/refractory ALL. And you can see here that it's a complicated schema but incorporates these 3 novel therapeutics that were all approved within the past 10 years. So the first being blinatumomab. This is a bispecific T cell engaging anti-CD19 therapeutic. It's given us a continuous intravenous infusion for 28 days, patients start in the hospital and then are discharged from the hospital with a bag that they carry around and they need to undergo multiple bag changes throughout the course of therapy. This is a very active drug in ALL, particularly in patients with low burden disease. The issue is that it's not curative is the response rates are very high and it does a great job of getting patients into remission, clearing measurable residual disease, but patients will invariably relapse after blinatumomab. The next therapeutic is inotuzumab. This is an antibody conjugated to chemotherapy. It's directed at CD22, which is expressed on most B cell ALL. This drug also is associated with very high response rates, but also is not curative in the current form. And finally, the newest agent that was approved just in fall of 2021 is brexa-cel or Tecartus. This is the first CAR T cell therapy that was approved in the adult ALL space, and we're going to go through it in a bit more detail in subsequent slides. I do want to point out from the NCCN guidelines on the right that you can see here that each therapeutic pathway ends with allogeneic hematopoietic cell transplantation. And so the current paradigm in relapsed/refractory B-cell ALL in adults, remains using these therapeutics as a bridge to a definitive therapy such as ALLO transplant. Next slide, please. So here we get into just a little bit more about blinatumomab and inotuzumab and showing data here on the left from the tower study, a randomized Phase III study, which led to the approval of blinatumomab compared to standard chemotherapy in the relapsed/refractory adult B cell ALL setting. Here, we have the INNO2VATE trial results on the right of inotuzumab. You can see here that patients do have high response rates, overall response rates with inotuzumab, ranging from 70% to 81% with blinatumomab in approximately 40%. However, as you can see from these curves, most patients do relapse without the use of transplant as consolidation. I also want to mention the toxicities with these 2 therapeutics. So blinatumomab does cause in some patient cytokine release syndrome and neurotoxicity, which we see also with this CAR T cell therapies and inotuzumab has a very unique toxicity that is a result of the chemotherapy that is conjugated to the antibody. And that's veno-occlusive disease or hepatotoxicity. And this is actually a very big deal when you're using this agent as a bridge to transplant because transplant itself is associated with this hepatotoxicity. And so we worry a lot about buying inotuzumab in this setting and some physicians will avoid this drug because they're very worried about what it may subsequently do to deliver. The next slide, please. So brexa-cel or Brexucabtagene autoleucel or Tecartus. This is a CAR T cell therapy directed at CD19 was approved by the U.S. FDA in October of 2021 based on the ZUMA-3 trial. Notably, the ZUMA-3 trial was a Phase II study that infused 55 patients with this therapeutic, 54 patients evaluable. On the left, you can see the response rates and the toxicity rates of these 54 patients. The overall response rate, which is CR or CRi was 65%. Notably, this therapeutic is associated with high rates of Grade 3/4 cytokine syndrome and neurotoxicity. So you can see the grade 3 or higher CRS rate of 26% and Grade 3 or higher neurotoxicity of 35%, 40% of patients on this study required the use of vasopressors to maintain blood pressure. I want to speak for a moment about neurotoxicity in CAR T cell therapy. This is a big deal for our patients. Grade 3 or 4 neurotoxicity requires very high doses of steroids and these patients become very debilitated. So any therapeutic can avoid high rates of neurologic toxicity is very welcome because subsequent to CAR T cell therapy, sometimes these patients have to go to rehabs and of course, steroids increase the risk of infection. So the question also becomes in terms of efficacy with brexa-cel. The response rate of 65% is exciting, but are these responses sustained. Next slide, please. And so the previous slide was published. The top line results of the ZUMA-3 were published in the Lancet a year or so ago. But the company and investigators have subsequently updated their data on these 55 patients numerous times. And here, we see the most recent update, which has approximately 38.8 months of median follow-up. And now we get a look at what's actually happening with these patients over time. And I want to draw your attention to the bottom left box. So of the 39 patients who achieved a response CR or CRi to this CAR T cell therapy at 38.8 months, 4 are an ongoing remission without the need for subsequent therapy that includes transplantation. And so when we think about is this CAR-T cell therapy definitive curative therapy on its own, what we really end up with is essentially 4 out of 39 patients in remission. And so we do have a lot of work to do in this space to improve the durability of response to CAR T cell therapy in adult ALL. Next, please. I am a physician who does allogeneic hematopoietic cell transplant. I think there is a role for this therapeutic. But there are very specific and important toxicities associated with transplantation for particularly younger and older adults. Currently, as I mentioned before, all of the therapeutics that have been recently approved really, for the most part, serve as a bridge to transplant. While transplant can cure some patients, it's not always curative. And some of the toxicities that we really worry about are chronic graft versus host disease, which can be a debilitating lifelong toxicity. In young adults receiving transplant, it does render them infertile, which is a very big deal in our young adult population. In older adults, many are still not even eligible or offer transplantation. So the field of adult ALL as well as pediatric ALL is really trying to find therapeutics that can take the place of ALLO transplant in the high-risk or relapsed/refractory space. And that's where we're very excited about CAR T cell therapy, particularly very active, durable CAR T cell therapy because we're trying to move away from this paradigm of using these therapeutics as a bridge to transplant. But what we really need is a therapeutic that can demonstrate ongoing efficacy. Next slide, please. So I believe this was the last slide, and it really just summarizes hopefully, what I just shared in the last 5 to 10 minutes, which is that despite new therapeutic agents that are really exciting, there does remain a significant unmet need in patients, particularly adults with ALL. Our standard of care therapy is in the relapsed/refractory space, including blinatumomab and inotuzumab are associated with high response rates, but have limited durability. Brexa-cel, which is our first CAR-T cell therapy in the adult space directed at CD19 is an alternative treatment for relapsed/refractory B cell ALL, also associated with high response rate bases, but quite high toxicities, particularly high-grade neurotoxicity and limited durability. So neurotherapies may provide an opportunity to address some of these limitations without the need for subsequent transplant. And I hope that's what you're going to hear a bit about today. And I'm happy to take questions or anything that's useful. Thank you.

I'm happy to do that actually clear. So it sounds like we don't have questions at this point in time. There's obviously opportunity for questions later on. I would like to first thank Lori for a fantastic presentation introduction to the disease, the medical need and the challenges that we're facing, treating these patients that help us they are in very significant need of additional options, therapeutic options. So I'd like to thank you for joining and are going to actually move now to the second conversation, second part of the talk. And this is actually going to be held by Claire Roddie. And I just want to briefly introduce Claire before we're going to go into our presentation. Claire is a consultant hematologist at University College Lambton Hospital and Associate Professor in Hematology at UCL, with a particular interest in adoptive cell therapies. Claire has completed a PhD at UCL with Professor Karl Peggs and subsequently undertook a clinical scientist role with Martin Pule, who some of you obviously know as Chief Scientist also at Autolus and obviously, running the CAR T program and has established a CAR T program at UCL. Subsequently, and what we think we cleared and have gotten obviously, more responsibility within the cell therapy activities at UCL and her current role involves the preclinical development of novel cell therapy projects, the GMP manufacturer within the university clean room setups and clinical trial design and conduct. And she's also responsible for the Advanced Therapies clinical service at UCLH. And I think it's important, obviously, also from where we are to acknowledge that Claire obviously has been instrumental in the development of obe-cel and we'll also present the Phase II pivotal data of obe-cel at ASCO, as we announced earlier today in one of our press releases. The presentation will be held on June 2. So with that, over to you, Claire, and an introduction to obe-cel.

Thanks very much for the kind introduction question. And if we could move to the next slide. So we'll talk a little bit about obe-cel. I think a lot of people on the call will be familiar with this CAR. It's quite unique in the sense that it has a slightly different binding kinetic to CD19 compared with some of the other commercial binders such as FMC 63. So by virtue of it coming off target slightly more quickly, it means that there's less in the way of cytokine secretion per target interaction. And as a consequence, we've seen less in the way of cytokine mediated immunotoxicity in our treated patients. And what's more by virtue of that fast off kinetic, these cells actually appear to persist and survive longer in vivo. So these are the sort of the unique properties of this binder that was developed at UCL and then develop further through Autolus. And so you can see there's a bit of preclinical data on the slide here, which speaks to that piece, this sort of this unique binding kinetic results in enhanced cytotoxicity and actually proliferation in vitro. And if we move to the next slide. So this is a schema of the ALLCAR19 Phase study. So with this hugely promising preclinical data set showing this novel binder with this improved cytotoxicity and the sort of essentially very preferential profile. We decided to test it in really a very high need patient population, and that's those with relapsed and refractory adult B-ALL. and so the patients who came on to this study essentially were screened. They underwent a leukapheresis because, of course, this is an autologous CAR T product. And during the manufacture period, and those patients would have bridging therapy as was indicated according to disease burden. And then when the product was ready to infuse, they were admitted to our unit for preconditioning with cyclophosphamide and fludarabine. Now in terms of the administration of the CAR T cell product, essentially, it was a split dose, so we would give the initial dose on day 0 and a second dose on day 9 in the absence of any immunotoxicity in the intervening period. And so the dose was also dictated on day 0 by the burden of disease in the bone marrow prior to the lymphodepletion. So patients with higher disease burden would receive a slightly smaller initial dose on day 0 and then have the top-up dose, if you will, on day 9, whereas patients with lower disease burden and that was defined as less than 20% last would have a higher initial dose on day 0, followed by, again, a top-up dose on day 9. And our first assessment of disease response was performed on day 28 and then patients continued in efficacy and safety follow-up until the end of study. We move on to the next slide, please. Now in terms of our initial experience in relapsed and refractory adult ALL, I think this speaks for itself. So essentially, we treated 20 patients on the CAR19 Phase I study. And you can see that whilst we did see some CRS. We didn't actually see any severe events, so we didn't see any Grade 3 or more CRS in the entire patient cohort of 20. We did use tocilizumab in 35% of patients, but all of those had a grid to CRS. And there was no steroid used for the management of CRS on this study at all. And in terms of ICANS and Lori spoken eloquently to the implications of ICANS in other CAR T products. Well, here, we did see some ICANS events, so 20% of patients developed any great ICANS with 3 of those patients, that's 15% developing a grade 3 event. But again, what makes this a unique situation is that really all cases rapidly resolved within 24 to 72 hours of administration of corticosteroid. So it was very swift to respond to appropriate intervention. And what's also notable is you could predict who would get ICANS. It was the patients who had the higher proportion of blast in their bone marrow prelim depletion. Can we move to the next slide, please? So I think what you can see on this slide is a summary, if you will, of the responses on the study. So on the left, you've got a swimmers plot, which everybody will be familiar with charting the individual patient progress for those 20 recruited patients on the Phase I study. And we have high initial response rates. You can see that out of those 20 patients, 17 achieved CR or CRi, that's 85% of patients. And a significant proportion of those patients achieved durable remissions without any other therapy. And on the right-hand side of the slide, this is broken down really nicely in this pictorial representation of the patient journey. And actually, 7 of our patients are an ongoing remission without any further therapy. And I think this is probably quite unique in the adult B-ALL field. So if we can move on to the next slide, please. I think this is probably the piece that we feel is very important to how obe-cel works and how we see these sort of protracted remissions without further therapy. The fact is that these CAR T cells, probably by virtue of this fast off-rate CD19 binder, they are able to persist in the patient bloodstream to the point where we're able to detect them by flow cytometry even up to 48 months and in some cases, beyond for certain patients. So this is a product that is really unique in terms of its ability to persist in the patient blood stream. And all of our patients who remained in remission without further therapy, notably all had ongoing CAR T cell persistence. And you can see on the right-hand side of the slide, this is a very sort of a gratifying Kaplan-Meier curve, showing us the event-free survival. And you can see this nice plateau that seems to emerge at month 12, which is ongoing with no further relapsed events. So giving the impression that if you get to that sort of time point that 12 months post infusion, that perhaps this may represent a durable and long-lasting response for your patient. Next slide, please. So this is a little, I guess, a sort of a description of where we went or where Autolus took us after the Phase I UCL based study. So Autolus took on this cap CAR binder, this obe-cel product and have delivered or are delivering a Phase II global study with 34 sites across the U.K., across the U.S. and across Spain. And initially, we ran the Phase Ib run-in study, and that completed at the end Q4 2021. And we've got the Phase II study in the interim analysis that completed in Q4 2022 and very satisfying that the primary endpoint was reached and that was determined at that point. And the Phase II cohort is now fully enrolled as of Q4 2022. And of course, as Christian mentioned, we'll be talking about some of our findings in a month's time at ASCO. So could we move on to the next slide, please? So -- and this is just again a little summary of the obe-cel FELIX Phase II data track, and this is at the interim analysis. And again, it was very important for us to understand that the Phase II patient outcomes were mirroring what we were seeing in the Phase I study. And I think you can see on the right-hand side of the slide, sort of the summary of the overall response rate. And you can see that 70% of our patients, and that's an equals 50. So 50 treated infused patients, 70% of those achieved a CR or a CRi. And again, looking and focusing really heavily on the toxicity, we can see that the CRS Grade 3 was only noted in 3% out of that 92 patients who were evaluable for toxicity. So again, an incredibly low CRS rates compared to competing strategies out there. And in terms of icons, greater than Grade 3, again, only 8% of patients experienced this toxicity. So we think we can sort of all see very clearly that there is a mirroring of what we experienced in the Phase I study, and we're very encouraged by this early interim analysis, I'm very encouraged to be taking this product forward. Next slide, please. And so again, this is just really to give an even broader picture of how consistent the obe-cel data is across all of these, what are independently conducted studies. So we're looking here at overall response rate. We're looking at CRS, grade 3. We're looking at ICANS. And what you can see is CARPALL, which was our pediatric B-ALL study, our Phase I study conducted at UCL, led by Persis Amrolia. You've got our old CAR19 study conducted at UCL with myself and Karl Peggs and of course, BLX1B and then the pivotal FELIX trial. You can see across the board, the consistency there in terms of overall response and in terms of toxicity. So I think that this is very encouraging for us to see in taking this product forward. Next slide, please. So I think to conclude, there's lots of information that we've shared today, but very much obe-cel. It is a differentiated CD19 CAR-T treatment in full adult and B-ALL, particularly in this difficult treatment landscape we find ourselves in with these really very cool morbid and rail patients often. And based on the mechanism of action of this CAR driven by this fast-off rate, we think that this CAR product has unique properties that aren't recapitulated with other therapies. And I think the CAR19 study really has demonstrated to us that CAR-T persistency is really important for B-ALL because 7 of those 8 patients in long-term remission, they all have ongoing CAR T cell persistence at last analysis. So in a sense, it's sort of feeding into that narrative that it is protecting the persistence is protecting patients from relapse. Now obe-cel has, and this is probably one of the biggest selling points for this rail population. It has a really favorable safety profile in these patients, and we didn't really see much in the way of grade 3 toxicity, hardly any grade 3 ICANS and certainly new grid 3 CRS on the ORCAR19 Phase I study. And again, the interim analysis that FELIX suggests a very similar profile. So the FELIX study is generating consistent data as we've seen in all CAR19 and even across the CARPALL study and longer-term data from this FELIX study will be released in December 2023, and we'll have an initial release at ASCO and EHA in June of this year. So next slide, please. I want to now focus take the book slightly away from the physicians, and let's focus on a patient. This is going to be a short video, and this is actually one of my local patients at University College London and she presented to us was referred up with relapsed/refractory B-ALL after a bone marrow transplant and was really very high burden disease and a very, very difficult clinical scenario. And so we managed to enroll her in a clinical study of CD19 CAR T cells like UCLH and we'll let her tell you in her own words, what her experience was during that process. So thanks very much. [Presentation]

I would like to thank you, Claire and your patience for sharing this remarkable and inspiring experience with us. Before we move to the next section, we have received 3 questions for Lori, and we're happy to take them now. Alex, will you ask them?

Absolutely. So the first question is, how will the use of BLINCYTO and the recent long-term follow-up data in first-line consolidation as published at ASH effect or change the treatment landscape and the RR setting?

Thank you for that question. I think the questioner is referring to the ECOG 1910 study that was a late-breaking abstract at this year's ASH. I have gotten that question at several meetings, as have others. It's an excellent question. And my thoughts on the topic are that I actually don't think it's going to change very much the treatment of relapsed/refractory. We have a sense now that CD19 loss after blinatumomab is fairly low in terms of the proportion of patients that lose CD19 that would not be subsequently eligible for CAR-T cell therapy directed at CD19. So I think the -- so that's one piece. The second piece is that I think clinicians around the country are really struggling to understand what to do with that data because the backbone regimen that was used in the ECOG1910 trial is not a regimen that we used in the United States. And the blinatumomab was given very late, and the MRD level was quite high. So in practice in the U.S., a lot of patients do end up getting blinatumomab, but it's much earlier in the disease course for a much lower burden of MRD. So I have to say I don't think it's going to have a huge impact on sequencing of therapies. But I think that remains to be seen. The last point, of course, is that an abstract and a full publication are 2 different things. And just one last thing actually, what was presented at ASH was the population of patients that were MRD negative who got Lina. So there's a whole population of patients that were enrolled on ECOM910 that were not part of that cohort. So I don't think that giving blinatumomab upfront is going to solve the problem about ALL and sort of the need for more definitive therapeutics.

Great. The next question is, would you consider using CAR T persistence data as a proxy for patients who may need subsequent therapy? And what response rate would you expect for Tecartus and EMD plus ALL patients?

Okay. So those are 2 separate questions. The first one is related to persistence as a proxy for clinical care. That is, I think, the ultimately be a great goal. I think one of the problems we have with persistence in real time is that many centers are not tracking CAR T cell therapy CAR T cell persistence in actual patients. My guess is the beautiful data that Claire presented a lot of that is probably bank samples for clinical trial purposes that was run in batch at some point afterwards. At Stanford, we actually do track -- we do real-time flow cytometry for all of our CAR T cell therapy patients, whether they're on study or not. The issue is that flow cytometry is different than PCR. And with our current CAR T cell options, most of these patients are no longer detectable by flow by day 28. So it's really tough to use persistence in the clinical realm before we have sort of a certified test that we can reliably count on particularly a PCR test. The second question about, I believe EMD is referring to extramedullary disease. In the 55-patient ZUMA-3 study, which is currently what we have to go on, what we know is that patients with very high burden, bone marrow disease have worse response rates. And that's been true really across the currently available CAR T cell therapies in ALL, namely [indiscernible] as well as to Tecartus. It does appear that patients with extramedullary disease have responses similar to other patients. And we think CAR T cell therapy is a good option for patients with extramedullary ALL. So I think my expectation of response rate is that patients with extramedullary disease have relatively similar response rates as patients without extramedullary disease, but patients with very high burdened bone marrow disease tend to have lower response rates.

And I know that was a 2 in 1 question, but I do have another one for you. Briefly, how will you monitor patients post CR to determine if they need subsequent treatment or go to ALLO SCT?

That's a great question, a very clinically practical question, and I think one that we struggle with in real life. I struggle with medications all the time. And I have a really wonderful group of clinicians and investigators that we e-mail each other of these questions on a frequent basis about what to do with our patients. There's really nice work in blood cancer discovery that was published in the last year by Mike Pulsipher group, looking at around 100 and, I believe, 120 or so children treated with Kymriah for relapsed/refractory B-cell ALL, and they were able to show quite nicely that loss of B cell aplasia in combination with next-generation sequencing-based MRD provides a really good surrogate for who is going to have durable response versus nondurable responses. And so I think those 2 metrics are probably the closest we have. So if patients lose B-cell aplasia by 6 months or if they did not achieve a next-generation sequencing MRD-negative response post CAR. Those data have not been -- those endpoints haven't been looked at in adult ALL at all. And I'd love to think that the pediatric literature extrapolates perfectly to adults, but we know that it doesn't. And so I think that we need to see whether those 2 features are robust in adult CAR T cell therapy because it would help us to have the surrogate to know who's going to relapse and who's not. Right now, we're pretty blind.

Great. Lori, I know you're tied on time. So we're going to stop there. But for any other questions from the audience that might come up, I will follow up with you off-line, if that's okay.

Yes, I'm happy to take questions over e-mail or in another format, too. Thank you so much for having me end in a drop off because I have to go right in the hospital.

Thanks, Lori, for these insightful perspectives. We can go to the -- yes, perfect. We're now moving. And I think with this deep appreciation of both the physicians as well as the patient's perspective. We would now like to move to the important aspect of access to these therapeutic options and hear from Dr. Matthew Gitlin, a market overview and economic assessment of therapy in ALL and CAR T therapy more broadly. Matthew Gitlin, Founder, Managing Director of Blue Pass Solutions, started the company in 2013 after working in the industry in academia for over 20 years. He spent about a decade at Amgen working in global and European offices across various functions, including market access, pricing, contracting, health economics, outcomes research, supporting both research and commercial activities. Matthew holds a doctor in pharmacy from the University of California, San Francisco and a Bachelor Science and chemistry and biochemistry from UC Santa Barbara. He's also authored over 75 publications and is an assistant professor at UCSF as well as University of Southern California. Over to you, Matt.

My name is Matthew Gitlin. And I'm going to give you guys an overview of the market related to relapsed/refractory adult ALL as well as some of the health economic evidence surrounding the adult ALL population as well as specifically some of the key adverse events, both CRS and ICANs as well as the broader related adverse events and how they actually inform the economic. If we can move to the next slide. On the first slide here, you can see that this is the epidemiology of the adult ALL population. This is using SIA data. SIA is a very large national registry in the U.S. It's oftentimes the data source we're using to submit for FDA orphan designation and rare disease applications. So it's a very robust data set. We often use this to generate epidemiological estimates to identify how big a target size of a population is. And in 2023, as you can see on the left-hand side, roughly about 6,500 cases are estimated. Now that includes all ages of ALL patients. So when we look at that age distribution, we see roughly about half are going to be in the adult sector. So that's 20 years and older. The incident rate is about 1.8 per 100,000, but that does not reflect the relapsed/refractory population. Among that, adult ALL population, which is about 3,000 patients, the incident rate is only about 0.19 cases per 100,000. So obviously, we're getting down to a very targeted, very focused population that is relapsed or refractory. If we move to the next slide, I'd like to show you guys the payer mix of this ALL population. And so along an adult ALL population, this is a 5-year prevalent data. You can see that the majority of the patients are commercial. This is important because between Medicare and commercial in the U.S., reimbursement does differ. In the commercial sector, if I'm to focus on inpatient setting specifically, commercial payers oftentimes will reimburse upwards of 300% more than Medicare. Medicare is using the DRG-based system, which is much more strict and focused, and it oftentimes leads hospitals and providers to losing money and they're offsetting that with their commercial reimbursement. In the outpatient setting the reimbursement is oftentimes much more fee for service. If we can move to the next slide, I'll show you guys a bit more when it comes to the cost data. Now on the left-hand side, what you can see here is that about half of the treatment administrations are actually done in the hospital when it comes to chemotherapy. And in the adult relapsed/refractory population on the right-hand side, you can see that their costs increased quite significantly for an overall ALL population only be about $90,000. The adult ALL population that is in relapse is costing upwards of $30,000 to $35,000 more. Now this relapsed/refractory population is quite burdened. They're incurring oftentimes roughly about 3 hospitalizations during their treatment period. And that's over a course of about 90 days. So you can imagine the economics of that, right, being in and out of the hospital in the U.S. system, cost on these hospitals are quite a large amount of money. And oftentimes, as I showed you guys on the prior slide, if they're reimbursed by Medicare, they're oftentimes not being reimbursed in full, and they're offsetting that with their commercial reimbursement, which is far more advantageous. So hospitals and providers where the reimbursement is oftentimes shifting some of the financial risk to them like in the inpatient setting. And in some cases, outpatients, we must understand what is that economic implication to the provider. They're taking on some of that risk. So things like subsequent hospitalization, things like adverse events. These are factors and attributes that we want to offset and that we want to show that with CAR-T therapies potentially, we can avoid certain types of adverse events, maybe chemotherapy-related adverse events, maybe additional hospitalizations and subsequent treatment. This slide really demonstrates that the economic burden for the adult ALL population is quite significant. And this data, I would like to add is actually quite dated. This will actually come from a study that was done in 2015. Some of the recent literature in adult ALL patients, it's a bit limited, but what we are seeing now is some evidence showing that these costs have increased substantially. As we move to the next slide, I wanted to provide you guys with a little bit more context on the treatment costing. Now you're going to see all kinds of treatment costs. This is a micro costing analysis. So ultimately, this is not renewal data. And what we find is that assuming that first-line therapy is chemotherapy, on average relative to the treatment period, you're looking at about $0.25 million for that treatment period. This does not include things like adverse events. This does not include factors like other exacerbations of the disease that may lead to hospitalization. The second line therapy upwards could be of equal value, if not costlier, as you move to more targeted therapies, monoclonal antibodies. So ultimately, what we're seeing is the cost increasing in second-line therapy. This particular analysis is assumed inotuzumab as second-line therapy, whereas third line is actually assuming that the cost could go up quite substantially if you were assuming blinatumomab. Now these are costing per label. So many of these patients may not incur the total treatment duration. This gives you a maximal potential cost by line of therapy. But what it shows you is if a patient can actually go through every line of therapy and respond and perhaps ultimately relapse, the cost can exceed oftentimes $1 million. And it's important to appreciate the total cost of treatment as a patient starts and initiate and sales and reinitiate therapy because in the context of a CAR T upfront cost. We need to be able to appreciate how much cost actually is incurred over the total treatment time for current patients to put that cost into context. And we've seen this in DLBCL. We've seen this in multiple myeloma. Oftentimes, the total treatment cost for these patients is much larger than just the initial line of therapy or the targeted line of therapy, and many times the CAR Ts can introduce an opportunity to offset some of these costs. If we move to the next slide, I'd like to switch over to more of the adverse event side of things. So obviously, we have an appreciation for the total cost of care. But there's another aspect here, which is adverse event. Now with CAR Ts, obviously, they're prone to CRS and ICAN. But on this slide, what we're focused on here is mainly the CAR Ts, although they do incursion for depletion, some cytopenias, those cytopenias are acute and they're only associated for that initial portion of care, whereas a lot of the chemotherapy comparators that adult ALL patients are currently being treated with perhaps in the first line are resulting in a chronic exposure to potential infections and cytopenias as these patients incur continuous cycles. And as they go through each cycle, they're incurring the potential risk. And these infections and these are adverse events are oftentimes a significant proportion of the treatment cost. So you can see that in infection cost for some patients could be upwards of half the cost of treatment. So first-line treatment often times can cost upwards of $0.25 million, but if a patient incurs an infection and may upwards cost about $164,000. Cytopenias like anemia, neutropenia, thrombocytopenia, these, on average, can cost upwards of about $100,000, if not more. And then GI toxicity oftentimes associated with some of the monoclonal as well as chemotherapy can lead to chronic management of being using PPIs and other types of endoscopy procedures. So the adverse event profile, separate from CRS and ICANS is important to appreciate, not only CAR Ts may introduce CRS and Ian, but they're offsetting many of the adverse events that actually lead to the total cost of care being much higher with current chemotherapy and monoclonal antibodies. If we move to the next slide, I'd like to put a little bit more focus on some of the value of CAR Ts. We can appreciate that CAR Ts have a strong efficacy profile. And what has been shown on this line is a great example of how CAR Ts bring value. As I showed you in the prior slide, the adult RR ALL population is costly. They incur subsequent treatments, they fail therapy. What we also saw is that these patients incurred verse events. And so what we see on this slide is actually an economic model. This is done by a competitor CAR T called Tecartus which was recently approved in the adult ALL space. And what you find here is that they compared their product to 3 comparisons. They compared it to blinatumomab, inotuzumab and chemotherapy. And in their economic model, which was to measure the cost effectiveness of their product Tecartus. What they found was that their product was very cost effective. So if you look at the bottom row there, the ICR here was roughly $93,000 per quality at its peak. Now in health economic terms and in the U.S., oftentimes we don't use this, but groups like ICER do and ex U.S. groups like NICE and Amnon and payers and HTA do that we're oftentimes in the U.S. looking for an IC below 150,000. So what this slide shows you, even with linotumumab costing quite a bit and they had some different assumptions on the number of cycles incurred, is that we found that current CAR Ts are very cost effective. Now that's with a great efficacy profile and actually not such a good safety profile. So if we move to the next slide, despite the current CAR T safety profile, those CAR Ts on the prior slide or that CAR T evaluated was very cost effective. So you can only imagine as we improve the safety profile and improve the risk-benefit profile of CAR Ts, 15-care of outpatient setting, reducing the risk of CRS and ICANs we can really increase the value proposition for the use of these products and really improve it for the providers as well as for the payers. On this slide, I just want to point out that CRS and ICANS can cost a lot of money. This is particularly an analysis that actually micro-costed a clinical trial. So oftentimes, many of the CAR T trials are collecting HRU data, which is health care resource utilization data and they're monetizing so that they can estimate. Now what we found here was that CRS and ICANS in the DLBCL population, this was a study done on Bronze specifically. What we found was a CRS depending on grade can range from as little as $10,000 to as high as $100,000, $125,000. But what I want to point out is on the right-hand side, what we also identified was that a lot of times on CRS and ICANS occur, they're occurring together. So they're either occurring sequentially or they're overlapping. And when that happens, what we find is that the cost of the management can exceed almost $200,000. So even though the rates of these -- some of these events may be small, maybe at the higher grade, they're not at the lower grades. And lower grade with a meaningful cost and a higher grade at a low rate with a much higher cost. This is impacting the value proposition of current CAR Ts. This is leading to patients being treated in patient instead of potentially outpatient where there's more opportunity for better reimbursement as well as more opportunity to offset costs where the site of care is more cost efficient. But this is ultimately adding to the overall acquisition cost of current CAR Ts. And then it's an area where CAR Ts need to improve. Given the acquisition cost is high, the aim here is to offset these costs. If you go to the next slide. What you can see is this is a parallel type of study, but what this study is, is it's in the real-world setting. So that last slide was a study done in a clinical trial. This study was actually using claims data. The study actually ended up using 2 databases, I believe, the Optum data safe and the market scan data state. And what they found, despite the lack of codes for CRS and ICANs, codes don't exist for this yet, they use proxy methods, and they found that these types of events like CRS and ICANS, which is referred to here as a neurological event can lead to an incremental cost of about $30,000 to $150,000. That's very consistent with the micro cost being done in the clinical trials on the prior slide. So we're seeing a wide range of incremental costs for these events depending on grade, but it is translating into the real world, and this slide proves that the real world is resulting in an incremental economic burden. And these patients and the providers themselves are ultimately incurring the disadvantage of that. If we go to the next slide, I wanted to just point out to you that there's not a lot of data currently on CRS and ICA in the RR adult ALL population, but there was recently a recent systematic review done. And what they found was, and this did include the ZUMA-3 Tecartus trial. What they just find was that the CRS rates were pretty consistent to the DLBCL and MM population for some of the other CAR Ts. And what we found was that CRS at all grades was about 82% to grade 3, 27%. On the ICAN, obviously, Grade 3 was about 14%. This is consistent with Tecartus. Tecartus was 92% for all grades, 26% for Grade 3s for CRS specifically. But what this also tells you is that combined with the economic burden of CRS and ICANs, that this actually took away some of the value in that cost-effectiveness analysis. It takes away some of the value of Tecartus, despite proving its cost effectiveness and being high value, given its strong efficacy profile, this devalued some of its value as a result of having to incur some cost to manage these events that we're continually seeing with the current parties that are in the marketplace. If we move to the next slide, I just wanted to point this out further. This is another study that was recently disseminated, which actually attempted to compare the CAR Ts and their CRS and ICANS specifically in the DLBCL. So you can see that CAR Ts are competing. They're competing now on adverse events like CRS and ICANS. And this example here, Breyanzi, is attempting to do a very, very good job of showing how their improved safety profile could lead to a much lower cost. And what they found was that their adverse event profile only led to about a 4% increase in cost, whereas axi-cel, Kymriah and Yescarta led to upwards of a 10% increase in cost relative to the current acquisition costs. Now new CAR Ts, obviously, that can avoid this like Tecartus has not been able to do this, would eventually offset this and it would translate into cost offsets in the hospital setting to the payer, to the provider and ultimately would not incur that kind of erosion or add an incremental cost to the acquisition of the product. If we move to the next slide. I just wanted to close out. So I know I apologize for any technical difficulties, but CAR Ts and the RR population is a very burden population, not a lot of treatment options. And the introduction, obviously, Tecartus has provided some demonstration of value. But what we found is that CRS and ICANS in these CAR T-related versus events are still burdening patients. They're still burdening providers. And really, the value in this space and across a lot of indications where CAR T therapies or potentially TIL therapies are being used, is really the left-hand side is proving that durable and robust efficacy, that long-term effectiveness. That real effectiveness eventually. But it's doing it with a predictable safety profile. This translates into economics. You can see that CRS and ICANS are not low-cost items. They add up and many patients who are having Grade 3 events are paying upwards of half the acquisition cost of the CAR T to manage that. So having that predictable safety is really important. The population decision makers, they are the hospitals that are making coverage decisions where they're acting as the payer, the third-party insurers, the IDNs. They're ultimately focusing on a lot of these features when comparing CAR Ts, when comparing preference and positioning for therapies. And it's a key area where a lot of us is health economic and outcomes researchers are very much focused on. So I appreciate you guys the time and happy to take any questions.

Well, thank you, Matt, for this great perspective. And with that, we'll go to our final presentation where we're looking at the commercial road map for obe-cel with Chris Vann, our Chief Operating Officer. Chris is an industry veteran with 30 years of experience in both development and business roles, having joined Autolus from Hoffman LaRoche is Swiss headquarters, where he was responsible for leading the lung cancer commercial team and general management of the Tarceva brand. He has extensive experience in global life cycle management of oncology products as well as implementing marketing strategy at a regional and national level. This includes launching several oncology, immunology and transplant products in countries, including the U.S., U.K., China, Japan as well as more challenging areas of countries like Romania, Russia and South Africa. Chris holds a degree in toxicology and pharmacology from the School of Pharmacy here at University College London. And with that, over to you, Chris, for the commercial road ramp.

So thank you, Christian. Next slide, please. What I'd like to do to start off is just quickly frame the opportunity and the size of the market. And I'm going to do that in 3 dimensions. The first is to look at the epidemiology, then I'm going to look at a sales surrogate for the size of the market, which is Blincyto. And then I'm going to talk a little bit about the pricing. So next slide, please. As Matt alluded to, we all draw from the same epidemiology basis such as SIA and UCAN, and if you look at just the U.S., the EU4 and the U.K., there is approximately 8,400 patients newly diagnosed with adult ALL each year. Dr. Matthew took us very nicely through the treatment journey. And many of these patients, after an initial success may actually go on to relapse all basically have unresponsive disease and around 3,000 patients a year will end up in relapsed/refractory adult ALL in those markets. One thing I think that's really important is just to highlight that although the first indication that we will go after is the relapsed/refractory ALL indication, obviously, the product has an opportunity to move up the lines and potentially to earlier lines of treatment. Next slide, please. When we look to size of the market, we always look for good surrogates, and we believe that the sales of Blincyto are good surrogate. Why? There's actually a number of reasons for this. The first is that it's obviously got a similar mechanism of action being a CD19 T cell targeting agent. The second is that it's used largely in the same indication. So around 80% of the Blincyto cells come from adult ALL, around 20% of the cells from pediatric ALL. And very importantly, it's got a similar type of toxicity profile, tolerability profile. So what that means is it can be used quite broadly. And what we're seeing is an expansion of the number of treatment centers where Blincyto has been used. We're also, by the way, seeing that many CAR Ts are now also expanding the footwork of delivery for CAR T cell therapy. So both Blincyto and ultimately, obe-cel will be able to be used in a broader range of hospitals. If you therefore do some very simple math and on average, we estimate that patients received 2 cycles of Blincyto. That costs around $207,000. You end up clearly with an understanding that there's over 2,000 patient opportunity today with Blincyto with an expansion on a growing rate of around 24% in sales. Very importantly, as we've seen with many oncology products, Blincyto isn't what I would consider a direct competitor. I think ultimately, the challenge for Blincyto and obe-cel will be to determine the sequence in which they are given, but they may well be given in the same patient just in ultimately if you like the order of treatment may change as we get more information on overselling as we look at the relative merits of the treatments and build the clinical profile. The key competitor that was mentioned earlier is obviously Tecartus because there we do believe it will be a straight choice between Tecartus or obe-cel. Next slide. So we talked about the opportunity in terms of patients. The other important thing that obviously drives the size of the market is the sales -- sorry, it's the price. And here, what you see is the latest list prices for the relevant products. And the 2 most relevant obviously are Tecartus and Kymriah. And what we can see is that they've actually taken price increases since they have actually gone on the market, and they're currently priced at $448,000 and $508,000 in the U.S. The other thing that I think is important to note is if Blincyto is used early it will be used for around 4 cycles in responders and then the drug costs for Blincyto will actually approximate to a CAR T drug price. Next slide, please. So having framed the size of the market. What I'd like to do next is I'd like to just go through some of the key elements which drive market adoption and ultimately will drive leadership. Next slide, please. So I'm not going to rehash what was eloquently done by Dr. Roddie. But just to confirm the point that she made, we're seeing very consistent efficacy across a range of studies for obe-cel. And it's actually partnering with relatively low levels of toxicity, particularly Grade 3 neurotoxicity and CRS. Next slide, please. So what I'd like to build on is what Matt mentioned, which is that this actually has some really significant and practical consequences. So lower levels of ICANS and CRS, particularly Grade 3 and above has several potential benefits. Obviously, it's going to be a factor in physician choice. It will also improve the patient treatment experience and obviously make the treatment journey a lot less challenging. It will reduce the costs associated with managing adverse events, as Matt alluded to, but it also actually means that a more manageable product can facilitate the use in a broader range of hospital settings. And we've heard from Matt that one of the things we know is important to hospitals is actually the way in which they could administer the treatment and having a more manageable product will actually allow it to be administered in a broader range of ways such as potentially as an outpatient treatment qualifying for Medicare OPPS. Next slide, please. So we're clearly excited about the product. There's some really important upcoming data releases we'd like to draw your attention to. At ASCO and EHA, we're going to be presenting the FELIX top line data. And Dr. Roddie is -- we announced today Dr. Roddie's presentation time, which is on June 2. And then later in the year, we're actually going to be able to provide, hopefully, at ASH longer-term follow-up data and some sub-analysis of some of the patient types. And then the other really important thing is, obviously, the data will continue to mature so that by the time we actually get to market, we should be in a position to actually have a very good understanding of the long-term benefits of the product as well. Next slide, please. It's great to have a wonderful product, but we've seen from some of the competitors that a wonderful product that cannot be delivered or cannot reach patients does not actually help you to become a commercial success. So one of the things that's really pivotal for CAR T cell therapy is to build a very robust manufacturing platform and logistics platform to get to the patient. Now one of the things that's interesting about the FELIX study is it was actually conducted during the height of the pandemic, COVID pandemic. So this is actually -- when you see the data, this is actually one factor you should consider that we'll actually underline that we've established a very robust supply and logistics network, both for the U.K., but also for the U.S. and for Spain. We're happy to report that building on that foundation of clinical supply, which comes from our unit -- clinical trial unit in Stevenage. We're also now building a commercial manufacturing facility, and we're actually on track to deliver this to be ready for GMP operations in the second half of the year. The handover of the first clean rooms occurred on November 25, 2022, and we're currently in the process of qualifying the site. This facility will actually have the capacity to more than meet demand and we'll be able to supply in the first instance, up to 200 patient batches per year. And we're also on track to put together the CMC package for submission to the FDA for our BLA at the end of this year as per plan. Next slide, please. I'd like now to move to how we're preparing from launch, and I'm going to discuss specifically 2 issues and 2 areas. The first is center engagement and the second is that the distribution agreement that we announced this morning, where we have terms and understanding Cardinal Health for support to actually distribute that product in the U.S. So I'll explain what that entails. Next slide, please. One of the things that may not be known about Autolus is we've actually been engaged in establishing treatment centers since 2018. We're actually one of the inaugural members of the NHS advanced treatment therapy centers or ATTC, and that was actually basically a public private sector partnership, which actually helped to establish treatment centers beyond London. And some of the interesting things that came out of that, we check this, for example, for accreditation and establishing treatment centers, how the samples will be managed through hospitals, through the hospital pharmacy network and other interesting things such as inflammation for patients and so on and so forth. So that gave us, together with the studies that we are running a foundation of how to actually work with centers and how to collaborate to actually have the products delivered. Next slide, please. But our reach has actually obviously gone beyond the U.K. and building on that foundation, we're involved in a number of important initiatives that are actually shaping the market globally. And I'll call out 2 of these and explain their significance. The first one is the ASTCT 80/20 project. We're actually corporate counsel members of the ASTCT, and we're working together with them and other companies to actually standardize many of the aspects of delivering CAR T. The 80/20 being the 80% of what is done to establish the delivery of a CAR T should be standard and only the 20% as product-specific should be different. We also work closely with the Alliance for Regenerative Medicine, which is essentially just under 500 member organization, which sells itself the voice of cell and gene therapy. It's basically the biggest advocacy for cell and gene therapy. And we're very active in areas such as market access globally and regulatory guidelines and things like European legislation. And for example, my colleague, Brent Rice, sits as cochair on the Market Access Committee for ARM. I'm a member of the Board and the Treasurer and I'm also the European working group leader for AR. Next slide, please. So now coming back to some of the very obe-cel specific items. And one of the interesting things about launching a CAR T product is the essentially 2 launches. The first launch is a center -- the first launch is for the center and the second is the product. And typically, you need to actually be engaging centers around 12 months before you actually want to deliver the product. And the reason for that is actually getting them certified is a very complex process. In addition to master agreements, you need quality agreements, product handling manuals, trade policies, technical and medical qualifications, training for the product, training for patient support and a distributor agreement. And only if you have all of those in place, are you able at the time of launch to actually activate the center and sell your products. So typically, that process takes 10 to 12 months minimum. And then after the FDA approval, you can actually activate a site with the last remaining items such as the final account setup within a month. So we're actually going to initiate our U.S. center onboarding in the second half of 2023. We've built many of the components that we actually need to do that, and we're currently in the process of finalizing the team that will actually go and engage the centers. Next slide, please. Another thing that you might have picked up this morning, we made an announcement about an agreement with Cardinal Health, and I just want to cover the basis for that agreement. And the 3 key elements of that, some of which are common to CAR T cell therapies and some of which are very bespoke to Autolus. The first thing is that the Cardinal Health and the distributor, a traditional distributor, does not handle the product, but you don't need to work with them for a standardized set of services, which include things like flash ordering. So they received the order from the center. They'll do the center checks, government reporting of prices and so on and so forth. And those standard services are needed by all CAR T cell therapy companies, and they're an essential prerequisite to being able to both start onboarding but also to commercialize your product. The second area where we're aiming to work with Cardinal Health is in order to cash. Obviously, it's not in Autolus' interest to build an internalized revenue collection team. So we're going to work with them so that they can collect the U.S. revenues on our behalf. And obviously, the other companies that are already established CAR T players already have that internal, but that saves us from having to build that set of services. And the last thing, which is truly unique is that we will establish a depot model. And why that's important is we'll be able to maintain customer and storage of our products, but we will be able to move them closer to U.S. treatment centers while completing product release with an aim to actually reduce vein to delivery time. Next slide, please. So in summary, we believe that oversell offers high levels of initial ORR between 70% and 85% with the potential for durable responses as a stand-alone treatment. We're obviously going to release interesting data at ASCO, and that will further build upon what's known about the tolerability of obe-cel and improved tolerability, we believe, is not just important for the physician and patient preference, but it also reduces total treatment costs and has the potential to allow the product to be administered in a wider array of hospital settings. The foundation for robust and reliable supply was established during FELIX, particularly interesting was that we had to actually be successful during the COVID period to actually complete that study and so obviously, we had to ship to Spain, U.S. and U.K. during the height of COVID. And we're building on that foundation and the nucleus is on track to be GMP certified by the year-end, and that will provide our commercial supply initially for up to 2,000 patients. And then we're also putting in place the other key elements needed for competitive commercial distribution and center engagement like the Cardinal Health distributor agreement we announced today. And then finally, just to summarize as well, we believe that the initial opportunity is over 2,000 patients, and we've given the 2 price range, the 2 most relevant prices for the range where we expect the pricing to be. Thank you. Over to Christian.

Thanks a lot, Chris. With that, I'm just going to briefly summarize on the next slide before we go into Q&A. So we're at a very exciting stage I think, with the company. We have obviously come a long way, gone through a pivotal study, as Chris has pointed out to the height of the pandemic, basically started enrolling in July, around July 21. We ended enrollment in November 2022. So a very challenging period, not only from our perspective of manufacturing, delivering product, but very much challenging for the treating physicians, for the patients and the caregivers who were sort of managing and navigating a very challenging environment. We're really pleased to be able to actually get through that whole process, get the study done in this incredibly challenging backdrop and we're now getting ready for the presentation of the top line data at ASCO and are also planning obviously a presentation at EHA. We believe it's a great opportunity, obviously, as we go through the course of the year to give further updates, as Chris has pointed out also towards the end of the year with longer-term follow-up, but also looking at sub-analysis and a more detailed understanding within the study, I think there is a lot in there that we'll be able to talk to as we sort of progress our understanding of the product. Now from a manufacturing perspective, Chris was pointing out, obviously, absolutely critical to be able to deliver product. We know that this is obviously crucial. As you can imagine, as we went through the pandemic, this was an enormous pressure test. Just to give you one number, at the peak of the pandemic, the transatlantic flights were down to 5% of normal and we still managed to deliver product in time for every patient at every site in the U.S. So you can imagine our logistics team has been on an enormous learning curve, and it's gotten exceptionally good at being able to actually deliver product. The same holds true for the manufacturing team, obviously, just to give you a sense for what it takes to actually manufacture for this type of a study. We did operate 2 shifts a day, 7 days a week. We did that, obviously with separation of the teams, no overlap, lots of testing, as I think we all lived through that period. And we're able to actually deliver a very, very good outcome. And we're obviously we'll be disclosing our overall success rate on manufacturing as well as obviously our ability to those patients and compare that to the number of patients enrolled. All of that, I think, is very encouraging and speaks to the robustness of the manufacturing, the robustness of our ability to deliver product. And as Chris pointed out, we were designing our manufacturing facility for commercial applications as such that we can capture about 2/3 of the U.S. and European patients that are out there, pretty much covering kind of the same number of patients that today Blincyto is covering in the relapsed/refractory setting. And with that, should be in a position to actually support the patients, support the physicians and really match the demand that we believe is in this indication. Now just on a final point, obviously, as we're sort of moving the product forward, we're obviously also going through the regulatory process. One of the steps on the manufacturing side will be is that we're aiming for a GMP certification of the facility by the MHRA in the second half of this year, ahead of a BLA filing that we're targeting for the end of the year. Overall, we're in a good position. We have the cash to execute. We have the organization to do it and obviously, great support in the clinical community and for the product. And I think a lot of enthusiasm for a product that hopefully will deliver outcomes for patients in a way that doesn't require the patients to undergo the significant level of adverse events that they do experience in many of the other treatments that are available to them as they go through the course of their treatment journey. So with that, what I'd like to do is actually open up for Q&A. And we have Alex who has already started compiling your questions, and I think we can kick it off.

Great. So first question is for Dr. Roddie. 35% maintaining remission without further treatment is certainly a very attractive preliminary readout, albeit in a limited patient population. So as we think about the broader population enrolled in pivotal FELIX, where treatment effect could decline as the sample increases, what do you think is a clinically meaningful bar to target on this metric? And also to Dr. Claire and also to the Autolus team how predictable is the 6-month milestone of longer-term durability?

So maybe just before we get going, I just see Claire is muted. First of all, obviously, we're going to provide an update on the data and the FELIX data. I think what we have to do at this point is really build on the data that we have, and we can sort of project on that. And with that in mind, Claire see you're now unmuted. I'm handing over to you.

Yes. So just in terms of the questions asked. So could you -- sorry, could you remind me what the questions were again to the FELIX, because you've put 2 questions into one, please. Could you give me a question 1 again?

Yes, indeed, apologies. So the first question, a little bit like the 35% maintaining remission without further treatment is certainly a very attractive preliminary readout, albeit in a limited patient population. So as we think about the broader population enrolled in pivotal FELIX, where the treatment effect could decline as the sample increases, what do you think is a clinically meaningful bar to target on this metric?

Well, the bottom line is the population who are an ongoing remission in the Phase I study, they represent quite a sort of a mixed population in terms of disease burden coming in and age and so on. So the demographics are quite mixed. So I think it is a fairly sort of a heterogeneous population. So I'm hopeful that we will see the benefits of what we've observed in the Phase I ongoing into this Phase II pivotal study. And obviously, it's too early really to comment and I guess we'll have more information come June. But I think the predominant thing that we've observed is that it seems that durable persistence is associated with durable response. So I think for me, that's probably going to be the most important sort of biologic metric for success. I don't know whether or not Christian, any comments on that particular question, anything to add to that?

No, I think you covered it well. And as Claire indicated, obviously, when you think about the lead indicator here is really persistent because that's something you can see early on and you can get a feel early on of how the products are behaving in patients and clearly has been a very nice correlation that we've seen in the early work in the Phase I study. So that's certainly one of the things we're going to be looking out for.

There's also a follow-on to that same question. And this is to the entire team. So how predictable is the 6-month milestone of longer-term durability?

I think if you look at the data, and I'll let Claire respond to that in a sec here as well is when you look at the old CAR data, clearly, the data started to stabilize after 12 months. It didn't really stabilize around 6 months. But what we do have, and this is more from a regulatory precedence perspective is that the 6 months follow-up period was used for a number of prior programs in the space, including Blincyto and inotuzumab and was used as a way as a measure to sort of indicate a clinical effect that was sustained over at least a minimal period of time at the 6 months were that minimal period of time that I think was used in all of those programs. So it is more a question of precedence than it is, in my view, as a projection or allowing you a projection of what the product will do longer term and certainly also from the old CAR data wouldn't allow you to project. But Claire, please chime in.

No, I concur with that. I think it really was sort of the 12-month point of which we were able to see that sort of the plateau emerge. And I think in the CAR T field, 6 months is early to call it. So I would agree with what Christian just said.

Great. A question, maybe you can just comment what proportion of patients from FELIX do you expect will have at least 6 months of follow-up at the ASH readout?

Well, when we look at the data, as indicated, we had the 50 patients, which gives you a pretty good view. The 50 patients, we had the 3 months of follow-up that was completed as a data cut in the September time frame last year. So that's sort of the, give or take, the median of the study. And we obviously have an additional few months obviously until the data cut that we're now utilizing for ASCO. So we think that we're going to have at least half of the patients, if not more, that are beyond 6 months.

Great. The next question is for Claire. Please could you talk about typical bridging therapies received by patients in the trials?

Yes. So I mean, bridging therapy is probably an important component in terms of intention to treat sort of get a patient to the start line with lympho deflation. And our standard practice has really been to go quite light on bridging. We've usually used vincristine and dexamethasone for most patients to try to get them through that month pre-LD. On the ALLCAR19 study, that was the predominant method used. We actually used that out there were 18 patients bridged overall and about -- it was certainly over 10%. I think it was about 13 and 14 patients got Vin index. There were a small proportion of Philadelphia positive patients who also have ponatinib. And I think that's -- it's a nice sort of option to have for the Philadelphia positive patients. So you're not creating more in the way of Maru toxicity. So if you can get away with the TKI, you were good with that. Inotuzumab again, we use that sparingly because we were a bit concerned about potential impact on the sort of CD19 populations coming into lymphodepletion. It was used quite sparingly, but it can also be a valuable tool in the bridging arsenal and perhaps if you use slightly less than full treatment course and perhaps at a lower dose than would be recommended for standard even therapy. But I think that represents our kind of arsenal of treatment for bridging for adult patients coming in to CAR T therapy and what we did on the Phase 1.

Related question for you, actually, Claire. Looking at the FELIX data, can you believe -- do you believe you can also relate disease burden with the higher-grade CRS and ICANS and which therapies have you used as bridging?

Well, we talked a bit about the bridging therapies that we've commonly used in the previous question. In terms of -- I mean, I can't really speak to the Phoenix data because, obviously, that's at the moment is being sort of analyzed with the [indiscernible]. We'll look in more detail in June. But on a CAR 19, I mean I can't speak to that because we obviously we did see CRS on the trial. It was 55% of patients, actually, it was 11 of our 2 cohort. They got any grid CRS. And those patients of those 11 patients that were 10 of them have more than 5% blast. So had the definition of morphologic disease pre lymphodepletion. So it all sort of tally with disease, the incidence of immune toxicity. And it was the same case for the ICANS, and we touched on that in the slides as well because we've got 4 patients who developed neurotoxicity and all of those patients have more than 50% last. So I think you can, sort of, to some extent, reliably comment that burden, you're more likely to get toxicity. But I think what we have to remember here is that we didn't see any grade 3 toxicity. So even though we've got half of our patients have got more than 30% blast in their bone marrow pre-lymphodepletion, we're not seeing any grade 3 CRS. So I think that's the important take-home message here. And also with the ICANS, despite the fact all these patients had very heavily infiltrated bone marrows, we were able to sort of turn that ICANS process off really quickly with corticosteroids alone. So I think this is what sort of distinguishes this treatment and makes clinicians like myself and Lori and others more comfortable considering obe-cel in patients with high disease burden and more comorbid patients.

Great. Next question. With what length of follow-up from the FELIX study would it start to be reasonable to compare duration or response as a percentage of OS with results from ZUMA-3, which is now reporting MedOS of 26 months?

Yes. I think it's a good question. Obviously, we need to have a similar type of follow-up if you want to do proper comparisons because we want to make sure that these curves are properly mature, particularly on the later time points and you want to have a reasonably stable curve at that point. So as Chris was pointing out, by the time we're going to be launching the product, we'll definitely have that level of follow-up that will give us very clear views. I think what's interesting to point out, and I think Lori has pointed to that as well is that, overall, obviously, there's a very limited number of patients that do have true longer-term follow-up and without additional therapy. And so when you look at that, you do realize that there is virtually all patients have actually relapsed by about 24 months, which means that whatever you buy in terms of actually long-term outcome is a consequence of subsequent therapy. And that obviously makes also the interpretation, I think, of the data, particularly at the back end, rather complex because you're really actually having primarily an impact of other therapies that you're actually watching rather than the therapy that you actually have given. And that's why we started to look also in the ALLCAR19 study so much more on to those patients that actually did not require any additional anti-leukemia therapy, because that is really can be attributed then to the actual CAR T therapy that was given, and you can actually have a -- be sure that what you're looking at actually is related directly to the therapy. So that's just one thing to sort of keep in mind. I think we're going to get a much better view as we're sort of getting into ASH and then middle of next year, where we're going to start to have I'd say substantial follow-up. But I think important for us will be to understand actually the number of patients or the percentage of patients that will be in ongoing remission without any additional need for therapy. So that's going to be kind of the key to look out for. And it sort of, I think, also, I think, relates back to what Lori had talked about is obviously the reality that with the current standard of care, you still actually -- if you want to get a long-term outcome, need to get these patients actually on the stem cell transplant if you want to be able to extend it with the fundamental challenge to a lot of these patients already had a transplant. And so actually doing a second transplant is often very difficult, particularly if your patients are older, and there is a very substantial risk of treatment-related mortality for those patients as well. And we do see also some differences in terms of the propensity of using a second transplant also between different regions. And also there's definitely differences across age groups where there's certainly more of an ability to do that in the younger age versus the older age population.

Thank you, Christian. In ALLCAR19 and FELIX, what percent of patients received the first dose but not the second dose? And what influenced that decision to not give the second dose?

That's an excellent question, and we will absolutely answer that question as part of the presentation at ASCO, but it's premature for us to actually comment on that in more detail, but definitely an important question, and we'll be able to give a satisfying answer.

Please clarify the scope of the FELIX Phase II readout at ASCO. And should we anticipate preliminary duration of response over 6 months percent of EPS?

So obviously, we're going to be showing the full data set of all patients treated. So we're going to have a very, I think, deep understanding of the safety profile of the product, while a very good understanding of the overall response profile of the product. And we obviously will look at an early look at the durability information from the trial with the emphasis on being early because a lot of patients are still in that first 6 months of follow-up, which obviously means that the curves as we look into the later time points obviously become somewhat instable because there's just not enough patients at the outer time points. But I think you'll get a good sense and we'll start to -- obviously, we'll be able to show that at the conference, and we'll keep updating those curves.

Great. Next question, how closely related is ICAN CRS to blast count. And is it sufficiently strong to dictate patient management, for example, keep a hospital versus treatment community?

Claire, do you want to take a stab?

Yes. Well, I mean, I think we can quite clearly say, as we have already said on several occasions that ICANS in the Phase I study at least, there did appear to be a correlation with more disease. Clearly, we were able to turn that around really quickly with steroids, but the bottom line is that those were the patients and those poor patients did have more than 50% blast. Some patients, of course, is a bit like the patient video that everyone saw today. I mean some people have a very straightforward admission. And you can sort of see how maybe the patients might sort of divide out into cohorts that could be readily treated in a community setting, that's initial observations and feeling from having conducted the Phase I study and again, probably for Phase II and FELIX. We'll need to gather that data and have a deep dive into that before we can comment.

Great. A carry-on question from that one is do you expect durability data to influence coverage decisions by payer?

Chris, do we have Matt on? Or are you going to take that?

Unfortunately, Matt has dropped off, so I'll take that. So firstly, I think what Matt clearly showed was that the tolerability alone is substantial benefit to payers in terms of overall cost of therapy. Obviously, we're going to have also a strong initial efficacy. And then if we have improved durability of response, that should actually have also an additional advantage to that. But I mean, the tolerability alone has got really meaningful value to both payers as well as physicians.

Chris, the next question is also for you. There were some issues with vector supply chains last year. How is Autolus ring-fencing issues like that?

So I think the important part here with regards to vector supply and frankly, any part of the supply chain is that you have to make sure that you obviously have the right suppliers and the right agreements in place. What helps us is that obviously, the amount of vector we need is limited. We're looking at an indication, as we pointed out, that at peak, we expect to serve about 2,000-plus patients between the U.S. and Europe. Given that number, that is actually an opportunity to -- there is an opportunity there to actually run this with very well-established technology. I don't need to actually make a leap in technology to get to higher volumes and to secure supply. So in that regard, we're actually in a very good spot. So we can use actually the technology. It's been very well tested, very well established. And we do have a very experienced and reliable supplier for Vector and I actually do not believe that we have any of the issues that we've seen elsewhere with other programs, which are predominantly actually driven by the fact that the volumes and the amount of ultimately vector that needed to be supplied was much, much higher which also required shifts in technology, and that adds actually risk and had added risk to the actual supply chains. We don't have that, and it's one of the benefits of starting in a smaller indication.

Next question in the queue is how do you plan to implement the current split dosing protocol in the commercial setting? Have you received any feedback from your peers regarding the split dose? And also, what is the strategy of grade 3 through 5 CRS neurotoxicity observed after first dose in commercial setting?

So maybe to start out, obviously, the dosing regimen that Claire and her colleagues started to explore in the old CAR study, and we've taken into the FELIX study gives us an ability to really do a tumor burden adjusted dosing because clearly, there was a very nice correlation between tumor burden and overall toxicity. So tumor adjusted dosing is an important aspect. And there is a second safety element, obviously, that was built in into the dosing, which is that before you actually give the second dose, you do a check for the level of toxicity that is still actually ongoing in the patient. And clearly, if you have a substantial amount of toxicity at that point based on CRS or ICANS, you wouldn't actually administer the second dose. Now one of the key parameters that will be able to report on at the conference is also actually how many of the patients got both doses, it relates back to the question that was asked earlier. And it gives you a very good view that actually for how many of the patients actually, you would be -- you would question or you'd ask yourself whether or not the second dose can be given. So we'll be able to answer that part with data, I think, very straightforwardly. I think what's important with regards to the ability to deliver. So the key point here is that the dosing regimen that's actually in place for this product actually puts the physician in control. You're in control because you measure the tumor burden before lymphodepletion, you know how you're going to dose the patient. You also, as Claire pointed out, already start to have a pretty good feel for the likelihood of adverse events in that patient as well. And I think that is an important aspect because when you think about your ability to manage the patient, manage your team, manage the resources, you need to know what to expect. And I think that is one of the really big advantages of the approach that we've chosen. And what I'd like to do now is actually hand over to Chris, just to give a perspective of how that's going to be looked at from a more commercial perspective on the payer perspective as was asked in addition in the question. Chris?

Yes. So I think one very important point is it's a single treatment administered as a split dose. And we've had various discussions with the payers, and they accept that as a principal and as an approach. As Christian says, you'll also get to see at ASCO, if you like, the way in which that was actually adopted during the clinical trial and therefore, the basis under which most patients we envisage will actually practically receive a dose, which is if they have the first dose and no adverse events, they'll go on and have the second dose as planned. And as Christian says, one of the things that's important also to the payers and the physicians is the degree of control and degree of, if you like, our ability to predict what the course of the treatment is going to be and how the patients will actually be managed through the treatment cycle. So Claire, I don't know if you also want to give a clinician's view there. But it's basically, it's a single treatment given there's a split dose. The physicians have the control and the confidence because they can actually intervene if necessary, if it was to be required withholding the second dose.

I think that's fair. I think that's fair. And I don't think it's unique that for this particular product in terms of split dosing. I mean, this is something that's been explored for ALL, new Pan studies and also in Spain. So split dosing is obviously a consideration for a disease, which is very visible to the incoming CAR T throughout the bone marrow and blood. So yes, I agree. I think and it gives patient confidence as well, knowing that we have this sort of toxicity sort of management profile, if you like, within the product. So yes, and we haven't -- I mean, in terms of logistics and so on, it doesn't interfere with the sort of delivery of the study. We haven't found it to interfere with easy delivery of the study.

And I think one other important thing is the way that we actually ship and all the logistics is actually sent as a single product, and the doctor decides prior to the treatment, what the split will be according to the tumor burden. So it does give the hospitals a degree of control and an understanding of the likely treatment course for the patient upfront, but also they can adjust as they have the first experience of the first dose.

Thank you. A comment came in. There may have been a misunderstanding earlier on in the presentation about the initial capacity at Nucleus, 200 patient batches per year versus 2,000. Maybe Christian, you might like to correct that. And then also how do we batch those 2,000 batches?

Right. So the initial build-out of the facility will allow us to manufacture at a capacity of 2,000 products a year and will give us really the opportunity from the get-go. The facility in and of itself actually will be able to deliver a higher number of batches than we've indicated. So this is what we'll be able to deliver for these patients.

Conscious of time, I think this will be our last question. And for the audience, if there's any additional questions that come in, happy to take those offline. This one is for Dr. Claire. What would you be looking for in the December FELIX update? What would be a clinically meaningful outcome? And what could be important in the subgroup analyses?

So I mean, looking forward to December, I mean, it speaks to some of the conversations we've already had. We want to replicate what we saw in ALLCAR19 because we sort of see these benefits patients in remission at month 12 going on to continue in remission at month 24 months, 36 and even coming up to sort of month 48. So I think it would be nice to start to see those patients coming through month 12, still in remission with ongoing CAR T cell persistence. I think that's going to be really the important sort of clinical readout for me. I just want to see that what's sort of been born at UCL and sort of been through this whole process that it can deliver in Phase II also? And what was the second part of the question?

The second part was what could be important in the subgroup analysis?

So I mean, there's so many aspects of the subgroup analysis. I mean we're interested to look obviously at the impact of disease burden. We're interested to look at sort of populations depending on age, and we're interested to see the impact of extramedullary disease. So these are the sorts of clinically relevant impacts can we predict from the get-go who is going to have a durable response versus not? Is CAR T engraftment, is peak engraftment important area under the curve for durability of response and with persistence important for the durability of response as well. So again, sort of feeding into all of those questions that arose from the Phase I study. So yes, we're really looking forward to deep dive into the translational -- the parallel translational research as well to really understand this product at Phase II. Christian, do you have anything to add to that, sir?

No, I think very well covered. I think there's an enormous amount, I think, there to learn, including actually the impact that we may see actually as a consequence of the challenges that the clinics are facing during the trial. We have many of the clinics that had to shut down, actually inclusion of patients for some period of time, couldn't operate properly, had all sorts of stress levels. Patients didn't want to travel if the infection rate was too high. That obviously has an impact on the condition the patients are in. There's probably a lot of information there that we can actually tease out. So we're really looking forward to doing that. And obviously, looking forward to, I think, a lot of additional, I think, learnings that we consider to take from the study.

That's it from my end. As we're at the top of the hour. I think we'll stop there. And again, a reminder to our audience, if any -- if you have any additional questions, please don't hesitate to reach out to the team here at Autolus. Thank you.

Claire, have your patience on, which was really impressive. And I think eye-opening to sort of understand what that journey actually means. I know it was great to have Lori on to give us the real of the background and a broader view in terms of the opportunity, the standard of care. And I think Matt gave us quite a good view and a quantification of what it actually means for payers, but also for hospital administrators, what it means to cover for intense levels of patient management due to adverse event levels where they're triggered by the therapy itself where they're triggered by the disease. And obviously, those have a very significant impact on the overall treatment costs. It's not just a product or the drug acquisition cost, but it's also managing these patients through these very difficult periods where they really are challenged by the underlying disease, the immune suppression that is a consequence of it. But generally weakened condition that they're in. And on top of that, dealing with the actual intensity of therapy that is required to tackle this very aggressive, very fast-growing disease. And that's really been sort of the fundamental challenge that I think we all faced in the spaces that we need on the one hand, an enormously active therapy. And on the other hand, we're dealing with frail patients that actually cannot take that high level of toxicity, it's been particularly the challenge for the adult population. The children obviously have more resilience, and this is why we tend to use even higher toxicity schemes and chemotherapy, which obviously are the reasons why we do see more cures with kids. Unfortunately, those levels of toxicity are lethal for many of the adult patients, which is why we are using lower levels of intensity. And as a consequence, there's just a much lower level of the presplit patients that are transitioning into long-term remission. And that sort of creates the challenge from a therapy perspective and to really manage these patients and find a window to sort of create this opportunity. And I think one of the key things, and this is, I think, was coming through, I think, comments that Lori is making, but also what you heard from Claire, is that clearly the patients that have very, very high disease burden obviously have -- are much more challenging to manage, but they also have less of a likelihood for a longer-term outcome. And I think one of the key things that we need to do is really move these patients and start treating them when the disease burden is much lower. And you can also -- you've heard Lori talk about levels of detection. And the fact that if you -- as the patients that they actually want to treat actually are below what's detectable actually by flow, if they have a choice. And so that's sort of an area where we're starting to obviously be more active in over time, looking at patients with so-called minimal residual disease. It's a key area that also obviously was sort of an important part of the development cycle for Blincyto and was a key part of establishing that treatment and actually gaining more time and more benefit for patients over time. And I think this is also going to be over time, a trajectory that will be on with obe-cel as well. So with that, I think we're going to close here. Thank you for your attention. Looking forward to seeing many of you at ASCO or EHA and discussing with you the data in detail and obviously, exciting times looking forward to the next few weeks and be able to talk in detail about what we've experienced in this Phase II study. Thank you very much.