All right. Welcome back to the 45th Annual TD Cowen Healthcare Conference. Marc Frahm from the biotech team, and we're really happy to have with us the next session from Adaptimmune, Adrian Rawcliffe, the CEO. Maybe, Adrian, you want to start off by just kind of giving a brief kind of level set of people's status update across the company, and then we can get into some specific questions. Yeah. Adaptimmune is an uninitiated engineered cell therapy company focused on solid tumors, proprietary platform and pipeline, and very proud of the fact that we have just approved the first engineered T-cell therapy for a solid tumor with the approval last August of Tecelra for the treatment of advanced synovial sarcoma. Tecelra is the first product out of our pipeline. Back up behind that, about two years behind, is a product called lete-cel, also for soft tissue sarcomas. Behind that, we have a pipeline of other engineered cell therapies targeting larger potential opportunities: PRAME and MAGE-A10 in partnership with Galapagos, and then CD70 back in our preclinical pipeline as well. We've been prosecuting engineered cell therapies for the last decade, pioneers in the space, and we believe really strongly in the idea that if you want to be in this space and effective in this space, then you need to control the means of production. You need to control the manufacturing until it feels Adaptimmune from the ground up as an integrated cell therapy company. That's what's enabled us to deliver on that first approval and now be delivering to patients in the commercial setting. All right. Thanks for the overview. Maybe, as you mentioned, Tecelra is now approved, which congratulations on that over the last six months or so. How many patients do you think that label, this initial label, captures? Tecelra is approved for patients with metastatic or unresectable synovial sarcoma who have received prior chemotherapy. There are probably about 1,000-1,300 patients diagnosed with synovial sarcoma each year. The majority of those, the vast majority of those, will either have undiagnosis or end up with metastatic disease. The target that we go after, which is called MAGE-A4, is in about 70% of those patients. The tissue type is about 45%. When you run all those numbers, there is likely to be about 400 patients each year, annually, in the United States who are eligible for Tecelra. Our view is that as many of those as possible should receive Tecelra. There is not anything else, unfortunately, for these patients. This is not a competitive space. Again, unfortunately for the patients, there have not been a rash of new therapies that have been approved in this space. In fact, Tecelra is the first approval for synovial sarcoma in over 12 years and, in fact, is the only product that's been approved specifically for synovial sarcoma forever, really. It is a place where we think deep penetration into that rare disease population is core to us. That is what we've designed our commercial organization to be able to deliver. Best way of thinking about this is rare disease oncology intersection for these patients. Okay. You have issued kind of peak sarcoma franchise sales guidance of $400 million, which is broader than just Tecelra. Can you walk through kind of the major assumptions that are baked into that? I think you started to touch on it there with patient numbers, but also kind of high penetration. How does the second product play in? How important is that? Do you expect sequential therapy? We set about thinking about how we would bring Tecelra and lete-cel to market. They are very similar products. Tecelra targets MAGE-A4, lete-cel targets NY-ESO-1. They have both completed their clinical studies, obviously with Tecelra. They both show transformational efficacy in this space. They both go through exactly the same commercial infrastructure to enable them to get to patients. There is almost 100% commercial synergy in the infrastructure there. That is why we think about this as a sarcoma franchise and both of these products. I referred to the 400 patients for Tecelra. There are about 1,000 patients for both of these products. There are more than 1,000 patients through both of these products. Because they go through exactly the same commercial infrastructure, there is very little incremental commercial spend to bring the second product through to market. Of the 1,000 patients, 400 are the Tecelra population, and then there's an incremental little 600 that are the lete-cel population. That's driven by the fact that there's an incremental portion of synovial sarcoma patients for lete-cel that have—and we've assumed only those patients who express the target for lete-cel, NY-ESO-1, and do not express the target for Tecelra, MAGE-A4. There's a significant number of patients in the myxoid sarcoma space. The reason for that is that whereas the MAGE-A4 and NY-ESO-1 target expression in synovial sarcoma is 60%-70%, in myxoid liposarcoma, the expression of NY-ESO-1 is almost null. It's probably north of 90%. Some people say there probably aren't patients who don't express some level of NY-ESO-1. That's how you get to about 1,000 patients. They go through that same commercial channel, and the testing paradigm looks very similar, MAGE testing or MAGE-A4 target testing. We have that established for Tecelra. We will put that in place for the launch for lete-cel. And we looked at the analogs and thinking about how many patients is it reasonable to get to for that 1,000 patients. There are not that many good analogs, but there are a few. There are some companies that have launched rare disease products into very high unmet need, orphan or ultra-orphan tumor types. One of them, for example, Immunocore with KIMMTRAK, I think demonstrates that where you have these very defined patient populations, you can address them with a relatively discrete footprint from a commercial perspective. The patients, unfortunately, do not have alternatives, and therefore very high percentages of patients should be on these therapies. That is what was borne out by the guidance from our physicians who have worked with us through the clinical trials and who are now at the ATCs where we are launching. When they are asked, "Well, what percentage of patients, of eligible patients, would you put on this therapy?" the answer invariably is, "All of them," because they are already highly selected for the target, and they do not have any other option. Okay. Of those 1,000 patients, you mentioned the synergy across the products is nearly 100% from a commercial operations perspective. Just where does that—how many of those 1,000 do you think you need to be treating on an annual basis to kind of make at least the commercial organization self-sustainable? Because we have seen that be an issue for some other cell therapies, not so much in oncology, but outside of oncology. The math is reasonably simple. The selling price of Tecelra is GBP 727,000. We have said that there is roughly a 70% margin on that product at any real level of cost. The commercial organization, we have said, costs between GBP 30 million and GBP 45 million in totality. Therefore, incremental margin per patient, you need to get to somewhere between 70 and 90 patients to make that work well, to deliver a contribution to the goal. Okay. Maybe I will go into some of the early launch experience for Tecelra. You are about six months in since approval. Just any things that have surprised you in terms of the contracting process with payers, with the ATCs being activated, just patient mix, anything like that that is surprising relative to where you expected it to be? I have this feeling that if I was—I'm obviously not American despite having lived down here for 25 years. I have the feeling if I was American about this, I would be jumping up and down and shouting a lot. I'm British, so all I'm saying is things are going really well. They're going as anticipated when we set out to launch this. What's the biggest surprise is actually that there haven't been that many surprises. It's been an awful lot of work. Again, this is a new field, trying to get a new medicine adopted in a field that is not used to having cellular equipment. There is so much pent-up demand from the physicians and so much anticipation for this that it's been fantastic to see the uptake on the treatment centers and the uptake on patients. When we set out to launch, we anticipated that we would be able to open 6-10 treatment centers last year. We were very successful at that. We opened 11. We've added a couple more subsequently. If you go on to tecelra.com, you can see all the treatment centers we've got up and running. We thought that we would be able to dose our first patient within three to four months of launch, given the timing and the time it takes to test and then to get the insurance coverage, manufacture, etc. We treated our first patient three months, three weeks after launch on Thanksgiving Day 2024. First patient was treated at Moffitt. If you want to understand what goes into that, there's a really good piece that Moffitt had done about what that patient experience was like and how the entire team came together in between two hurricanes to get that patient treated. We said that we would have our first revenues in Q4, but that you should expect them to be minimal. We subsequently disclosed that we'd increased to three patients. Somewhere between one and three patients' worth of patients were treated, and we'll have revenue. We anticipated that that would accelerate as we went into 2025, and it is accelerating as we go into 2025. We look forward to being able to give an update when we put out our K in a couple of weeks' time on the number of patients that were increased in the beginning of this year. From a payer perspective, things seem to be going very well indeed. Obviously, each of these patients is treated following a case-by-case negotiation with the hospitals. That having been said, over 70% of commercial and Medicare lives are covered by plans that have policies in place for Tecelra. Those policies are almost entirely covering deliverable. The label is a broad, useful label for us. More characterized by going as anticipated than any particular surprises. Obviously, that's down to the hard work of the commercial team who executed fantastically over the last six months. Okay. You mentioned you'll update in the next week or two the apheresis number alongside, obviously, the bit of revenue that will have come in in Q4. One of the other metrics is maybe a leading indicator of apheresis rate is testing volumes for the two different biomarkers you need, right, HLA and MAGE-A4. Can you speak to the adoption of that test, how that's gone so far, but also maybe what's on the to-do list to make sure that that continues to grow? We have our own diagnostics for both HLA and for MAGE-A4. It is very much worth pointing out that we do not anticipate many people will use our HLA test. That is because HLA testing is ubiquitous at these centers, and they all have ways of testing for HLA to the density to diagnose to determine what the patient has and why it is HLA. We do not see that much of the HLA testing. What we do see is we see a bit more, but probably still only the majority, not all, by any means, of the MAGE-A4 testing. We have centralized testing in place, and we actually have sponsored testing in place. It is free, for sites, and for patients. That centralized testing, we think, is picking up the majority of testing. Why is it not picking up all the testing? There are other non-commercial MAGE-A4 tests available. That is true. Some of the centers, you might imagine some of the larger centers, have, rather than use our centralized testing, bought that test in-house for themselves. They are running those tests themselves. We do see the majority there. That testing is going really quite well. We've deliberately not put out numbers on what that's looking. We did say that we had identified back in November about 15 double-positive patients already at that point in time, for whom Tecelra would be the next therapy, and we would anticipate that the majority of those would be dosed in the first half of this year. That testing continues to go well. Early on, it was clear we were seeing patients who had already been pre-tested in some form or another for MAGE-A4 because the MAGE-A4 positivity was very high. As the numbers have expanded, have increased, I think the positivity for MAGE-A4 is about where we think it should be in the 60%-70% range, but it was higher earlier on. I think the testing's going well. In terms of what we need to do to go forward, there's a sort of hierarchy and sequence in order to achieve our ambition for the product. First thing is getting the ATCs up and running, getting at least, we're now at 13. We want to get to 30 by the end of this year. Get to the patients that are in those ATCs or are going to get referred into those ATCs. Expand the testing out into the 100 sarcoma centers of excellence, then expand the testing out beyond that. We're also looking at how can we get the testing into the standard sarcoma diagnosis panels. Rather than just having the test for synovial sarcoma and translocation for synovial sarcoma, we would also have the MAGE-A4 and the HLA test as well. That, I think, is going to be key to getting out in the longer term. In the short term, I think it's worth pointing out, I think our objectives over the next few quarters are going to be met by executing on the patients that are already at or going into those treatment centers. It will be subsequent years where the importance of testing, which needs to be established now, but the importance of testing will play. Okay. With other oncology launches, we often see very rapid sales growth. Obviously, here you'll start kind of three to six months delay from a small molecule or an antibody. Then once the sales are happening, we see pretty rapid growth over the first year, maybe to two, and then it really slows down. It isn't fully at peak yet, but it's pretty close and pretty mature for that label. Should we expect that type of pattern here, or these dynamics of centers of excellence and ATCs, or should we expect a more prolonged launch, maybe a little less of an early slope and a better slope long-term? I think we see it at the moment, to the extent that we are able to predict this. We see the balance of ATCs coming on board and then testing, driving testing out into the other sarcoma centers of excellence in Vorna, leading to something that's probably not at the short end of that path. I think 12 months would be at the short end, 36 months would be at the long end. We would say not going to be at the short end. Consistent slope as we go through 2025 and into 2026. The other thing that I would mention is we do not have, and nor do we anticipate, significant competition in this space. I think one of the reasons why some of those curves flatten off is because as soon as there is another penetrant with small market dynamics, we do not anticipate that in the foreseeable future. As lete-cel comes to market, I think we will start to understand the dynamic of what happens with dual-positive patients and whether they go through Tecelra or to lete-cel. I think that we continue to work to maximize the number of patients that get there and maximize that penetration. I do not think this is going to be competitive for some subsections. It is worth doing. Okay. That's a good transition. You brought lete-cel up again. The company has said that MedEd's pivotal or our endpoint. I think data continues to evolve, and we haven't seen all that latest data. When should investors expect to see the next data update? Will that start to resolve some of these questions that you were starting to bring up for double-positive patients? How do these drugs live together? The dataset that we presented at CTOS last year was the primary analysis of that. I think we're going to have updates of those data, but that has all the patients in. The principal update is going to be therefore to the duration of response data, which we'll cut for the purposes of the pilot. I'm sure at some point we will update that. It's just worth pointing out how compelling those data were for lete-cel. 40%+ response rate in each of the sarcoma indications, equal response rate in both of them. A duration of response, which at that point in time was north of 12 months. Actually, for the synovial sarcoma population, it's more like 18 months. That will evolve, but it's a stunningly good duration of response for these patients. The other interesting point about those data, which we haven't seen so much, if you look at the dataset with Tecelra, there were two complete responses in that dataset out of 44 patients. Those complete responses were, interestingly, they're in the FDA, they're in the label data. They weren't in the primary analysis data. They're sort of like, they're sort of subject to whether they're complete or not, subject to the discretion or the judgment of the people doing the evaluation. We've always had anecdotal complete responses out of this study. With lete-cel, 60 patients, six complete responses. It starts to look like a little more than pure anecdote. Three in each of the subsets. That's effectively a 10% complete CR rate in a metastatic advanced population with average prior lines of therapy of three. That's a significant opportunity for those patients. That is a compelling dataset. How it will play out is really going to be subject to how the physicians interpret it. We look at the datasets, and they look very similar. The discussion is going to be probably for the patients who are dual-positive, okay, which target do you express more? Upset against that, Tecelra has a fantastic safety profile, and it will also have been established for a couple of years. I just think it is going to need to play out. The important thing to recognize from an investment perspective is we have not assumed, we have assumed only one of these therapies will be given. We are, relatively speaking, thinking that it should be whichever one the physician thinks is right for the patient. We have not assumed significant sequential dosing. We have not assumed, and it does not really matter whether a patient perceives as their self-therapeutic choice, Tecelra or lete-cel in 2028, as long as they get one of them and get the benefit from it. Okay. So implying there's because the manufacturing process is a bit different, right? I guess the push and pull is cost of goods is essentially the same. Okay. Is that something in terms of the sequential question, is that a dataset you intend to try to develop in the next few years to see if it works? Yeah. Give us time. I think we have anecdotes about it. Also, I don't think it's going to be worth doing an enormous trial to demonstrate this. We do need to generate evidence around it. It will be done in a more efficient fashion than large phase testing trial. I think it is going to be worthwhile understanding what will happen. There may well be opportunities for us to conduct clinical work and/or use real-world data to be able to support that. Ultimately, I think it's also going to be this is why we're not making this a large part of our investment hypothesis. I think there's going to be a discussion around the cost of that and whether people will pay for it, which is relatively expensive self-therapies. I think let's start with trying to identify the does work and then we'll continue. Okay. In terms of the ATC activations and where you would like to get to, does having that second product, as you mentioned, it expands the potential on-label population from 400 to 1,000. Is that needed to get some of these ATCs over the line of justifying kind of setting up the whole process at their center? We do not think so at the moment. We have been very pleased by the speed and agility of the centers who talk to people who have normal cell therapies. One of the things that they will say is how long it takes for some of these centers to actually stand up and get on board. We are super pleased. We have got 13 up and running at this point. They are some of the larger ones, and sometimes that might imply that they take a bit longer than they have. We think that we have the remainder of the network, which is 30 plus or minus. Do not shoot me if you want to go to 33, 35, and do not shoot me if it is 27 and we feel we are going to stop in there. Part of the rationale for that number is that this needs to work for each of the centers as a business. It probably doesn't work if you only have one patient a year. They do need to have a business that is viable with more patients. We don't think that any of them are waiting. We certainly don't get that impression from our discussions with them. I do think that when lete-cel comes through, it will leverage that network. The sites that are part of that network will get incremental benefit from having the expanded population. I think the uptake of lete-cel should be faster because of that pre-existing network in place as opposed to the Tecelra that we're building as we go. Okay. You mentioned the primary analysis was presented back at CTOS in November. Just what other kind of clinical and non-clinical data do you need to gather in order to submit the BLA for lete-cel? BLA for lete-cel will be a rolling BLA starting tail end of this year and going into the second quarter of next year. We applied for and received breakthrough designation for MRCLS earlier this year. That complements the breakthrough designation we already have for synovial sarcoma for this. That is important for two reasons. One, very simple, we should get a short six-month review cycle from filing to approval. The more important reason, which I think is the hidden benefit of most of these expedited review processes, is the ability to actually talk to the regulators. We did this a lot. It was largely unnoticed with Tecelra as a pharmaceutical was becoming Tecelra. You get to talk to the regulators, and they are on the hook for replying to you and telling you useful information. That is incredibly important. Because what that does is de-risk the file for us. It means that when we put the file in, we have a much higher degree of confidence that the FDA has signed off on it. Just one example. We had the process for how we would understand that we had qualified our vector effectively. We went to the FDA, and we said, "This is what we plan to do." The FDA said, "Yes, we'd like you to tweak that, do something different." You walk away knowing that your plan has been signed off by them. They said, "If you want us to look at the data before you submit it, we could do that too." We were like, "We want to do that too?" We decided, "Yes, we do want to do that." We submitted effectively all of the validation for the vector several months before we actually put it into the file. The FDA came back and said, "Yeah, okay." They had already seen a large chunk of that CMC module through before the data that underlies it, before they actually were submitted. That is hugely confidence building from an internal perspective. Specifically, what do we need? We need the clinical piece, which we have. We will do an update on the data. That and the preclinical submission will be the first pieces that go in tail end of this year. They'll be followed up by the CMC module next year for which we'll do what we did with Tecelra, again for lete-cel. I think it's that experience that we have from having done it previously with a very similar product that gives us the belief that this is the right approach and the right time. Okay. We are running up on time, but we spent all on kind of commercial and near commercial, but there is some pipeline work earlier stage going on. What should investors be keeping an eye out for from those programs? IND or CTA for the MAGE-A4 targeting user cell program, which has CD8 with it, so enhanced next generation CD8 in partnership with Galapagos. Anticipate filing that this year. Anticipate filing the IND for our PRAME program this year. Continuing to progress our CD70 program with a view to filing the IND next year on that too. Okay. Just on CD70 briefly, it's been talked about for a while as a target by the wider field. What's been learned about that target over the past year or two as some of these clinical datasets have read out from others that are going after CD70? How does the ADP600 differentiate from those? What's the kind of key factor? I think what has been identified is it remains the most broadly expressed cancer-testis antigen, this class of targets that are very useful for TCR, T cell therapies, because they are incredibly selective for tumors. PRAME is the widest, is the broadest expressed. It is expressed, obviously, in melanoma, where it is found, but it is also expressed in lung cancer and ovarian cancer and uterine cancer, etc. The wide range, probably the largest patient population. We have got the start of datasets, particularly in the melanoma space, which are sort of viewed as sort of low-hanging fruit because you have got very high levels of expression, and it is a very immune active cancer. There are a lot of immune therapies that are active against it. The key for us was to get to a place where you could target PRAME across a broad spectrum of expression. That requires a highly sensitive TCR. We designed our TCR to be approximately 10-fold more sensitive than the competitor TCRs, but it's just as selective. That gives the opportunity to hunt down to lower target levels of expression. We believe that that will play out in the ability to develop this in indications that maybe don't express quite as much MAGE as melanoma. This is based on our experience with what we saw with MAGE-A4 as well. I do think we have distinguished ourselves. We have the broadest range of responses in solid tumors with the MAGE and COR next-gen program. I think MAGE has the opportunity to do that across a wide range of tumors. Okay. Unfortunately, we're up at the end of time, so we're going to have to cut it off there. Thanks a lot, Adrian, for joining and everybody in the audience as well.