Hi everyone. Welcome to what I think is the last fireside chat session for the Guggenheim SMID Cap Biotech Conference. My name is Paul Jeng. I'm a member of the Biotech Research Team at Guggenheim, and I'm very pleased today to welcome our next presenting company, Adaptimmune. With us today is Adrian Rawcliffe, CEO. Ad, welcome. Yeah, great to be here. Great. Just to kick things off, Adaptimmune has a pretty good distinction of achieving the first-ever approval for a TCR T-cell therapy last year in TECELRA. Before we get into the commercial dynamics, could you provide a brief introduction to the company, how Adaptimmune got to this stage, and how TECELRA is now positioned to impact synovial sarcoma? Sure. Adaptimmune engineers T-cell receptors to be able to enable the T-cells to recognize cancer. When T-cells recognize something, they have a tendency to kill it. T-cell receptors are particularly good at finding targets that are on solid tumors. Everybody's aware of the CAR-Ts in the hematological malignancies. CAR-Ts work really well against cell surface proteins. There's lots of targets there in the heme malignancies: CD19, BCMA, CD20, et cetera. There are very few CAR-T targets in the solid tumor space. There are lots of TCR targets in the solid tumor space. We engineer those. All of our products in our pipeline at the moment are autologous cell therapies. They are cells from a patient engineered to be able to recognize a tumor given back to that patient. We have had the privilege of being able to build Adaptimmune from the ground up as an autologous cell therapy company specifically designed to do that. When we bring TECELRA to market, we are leveraging all of the capabilities that we have had and that product now, the first engineered T-cell therapy for a solid tumor, the first TCR T-cell therapy, and the first therapy in the sarcoma, synovial sarcoma space for over a decade. It is difficult to overstate the impact that is going to have on the people who are diagnosed with synovial sarcoma in the coming years. How does TECELRA fit into the current treatment landscape for synovial sarcoma? Yeah, synovial sarcoma is, to touch on what it is and how it is diagnosed, et cetera. 'Cause I think that's important to understand the level of medical need in this space. Synovial sarcoma is typically diagnosed in, by patients in their, when they're in their thirties. There's actually a sizable young adult and adolescent population who have synovial sarcoma. And it's a rare cancer. It represents 5-10% of soft tissue sarcomas as a group. There's probably a little over 1,000 people a year diagnosed with this in the United States. When you are diagnosed, chances are you know nobody who has this. Chances are your physician has never come across this or maybe once or twice in their entire practicing career. And so you have, you have no information. And you're often diagnosed much later than you need to be because when you're 30, I can just about remember when I was 30, if I got a pain in my shoulder, it was not obvious to me that I needed to get tested for cancer. You know, I'd probably pull my shoulder playing sports or something like that. People tend to leave it. They tend to get physio for their cancer, and then eventually they get diagnosed. Most patients, many patients are diagnosed with metastatic disease. When you are diagnosed with a local disease, you can get resection. Sometimes that has a curative intent, but it tends not to because it has already metastasized in reality. First line in treatment in a metastatic setting is anthracycline-based chemo, affectionately known by the patients as the Red Devil. You max out tox-wise after six to eight cycles if you are healthy, fewer if you are not. It produces responses. The responses are short-lived. After that, there is nothing in the second line setting that is efficacious. Into that, TECELRA comes. TECELRA has a 40% plus response rate, 43% response rate in patients. Those responses are deep and they are durable. 40% of those responses last for longer than a year. We have patients who are still in response several years after they've taken their therapy and some patients who have no detectable disease after that period. This is completely transformative for this space against a backdrop of, you know, not that much investment in the space. This is the first medicine in over 10 years. The options that are there are pretty dire. Great. TECELRA then was approved by the FDA last year. On the launch, you've been sort of talking about updates on early metrics, such as site activation, patients who have undergone apheresis. Can you remind us where you are today on those parameters and how that's been tracking, compared to your expectations? We projected when we got the approval, which was very beginning of August, that we would be able to treat the first patient three to four months after approval. That was based on our projections about how long it would take to get a site active, for patients to be tested, go through the insurance process, manufacturing, and then testing. That whole process can take three to four months. We were successful at doing that, very successful. We treated our first patient on Thanksgiving Day 2024 at the Moffitt Cancer Center down in Florida. Actually, the Moffitt have just put out a long-form article about their experience treating that patient. That patient was apheresed in the middle of one of the hurricanes that hit Tampa last year. It's just a great story about the efforts that center and the patient went to, to receive TECELRA. The other thing that we said is we wanted to get our network of treatment centers up and running. We estimate that there will be about 30 treatment centers in that. We previously thought that we wanted to do that by the time our next product gets to market, 'cause it'll go through the same treatment centers. And that's 2026 approval anticipated. We had great experience with the sites. The centers really took off. We thought that we would have between six and 10 centers open last year. We opened 11 last year. It's slightly outside the top of our expectations. There is a lot of demand from the centers. We have brought the timeline for center full network opening forward to the end of this year from the end of 2026. We looked at what other companies have done in terms of early metrics or metrics that can help people predict demand and where the sales are going to go. We came up with aphereses as the most useful one for everybody to be focused on. Number of patients apheresed, there are two things to think about between that and patient dosing. One is manufacturing success rate, and the other is time. Manufacturing success rate for us has been about 90% in the clinical trials. Time from apheresis to patient infusion has been six plus weeks. It is a fairly useful. It means the patient's tested double positive, they've cleared the insurance, they've got to an apheresis site and the last steps need to be done. We obviously apheresed the patient that we treated in November. We said that, by the end of 2024, we gave an update at the JP Morgan conference that we had apheresed three patients, which is about on track where we expected to be. We had previously given an update that said that the shape of the funnel behind that was looking really quite robust. Back in November, we said we had about 15 double positive patients and that we expected the majority of those patients to be treated in the first half of 2025. I think we are on track for a very promising launch. Now, having said all of that, it's early days and there's still much that we don't know, but everything that we've thought would happen so far has sort of happened as we planned. If that continues, I think we'll have a very good launch on our hands. Great. Maybe just digging more on the ATCs, the sites that you've stood up. You mentioned 11 sites as of end of December. I think as of today, I checked on, there's 12 listed as active or in progress. Do these sites serve approximately similarly sized patient populations? Are there some that are, you know, more important, I guess, in the grand scheme than others? Is there any way to sort of read through the pace of patient enrollment based on how fast you're getting the sites up? Yeah. So, the sites that we've got up first are a mix of the ones that we prioritized getting up first, and the ones where we had a really strong champion to drive the sites to be established. And, you know, there's obviously a decent overlap between those two. But, there's a mix, there's a mix there, that defines how quickly the sites get up and running. So it includes some of the larger sites because that's what we wanted to prioritize. And so if you go onto tecelra.com and you look at the map, you'll see Memorial Sloan Kettering and you'll see MD Anderson and you'll see University of Pennsylvania and Moffitt and Stanford. And these were high recruiting sites on our, during our trials and have really, are really eager. So all sites are not created equal. Even if they do serve similarly sized populations, the referral patterns are different. Obviously, sites like MD Anderson are very significant, and Memorial Sloan Kettering too. The approach going forward will be that we will steadily over the course of this year get the remaining sites up and running. The reason that won't be, it's not a terrible proxy for physician interest and for site interest. Our ability to do that, to get the sites up and running, is obviously critical to get patients treated. I think it would be a mistake to think that it's a linear relationship between the two. The principal reason for that is this is a highly engaged, very active patient group, and they're also young. The majority of them are commercially insured, and they are very active in their own care, and very high agency. We do anticipate that what we've seen in the first group of patients will continue, which is healthy referrals and patients willing to travel across reasonable distances in order to be treated. What we are seeing at the moment is if there are patients who are not in areas where the site isn't quite ready yet, those patients are getting referred, in some cases, to sites that are already stood up and getting treated at those sites. Obviously, there are some where the site opening is imminent where they're saying, I'll wait, I'll wait a couple of weeks and do that, do it then. I think it's more complicated than a linear picture. Got it. Okay. So then on patient ID, are patients typically tested for HLA haplotype and MAGE-A4 at any point in the diagnosis or only typically once they progress on that initial therapy? In other words, you know, are the patients that have been found to be double positive, could some of them be still a little bit ways away from possibly getting afami-cel? Really, really good question. The majority of patients at the moment are being tested with a view to going on to TECELRA in the relatively short term. It's not all of them, but it's the majority. However, it is our intent to drive the treatment earlier in the treatment of these patients and the treatment course of these patients. The ideal for us would be that when a patient is diagnosed with synovial sarcoma, their HLA status and MAGE-A4 status are known at that point so that the treating physician can chart the best course through the therapies that are available. To that end, there are groups that produce, that do panels of testing for sarcoma that will tell you which type of sarcoma you've got. We are seeking to get the testing introduced to those panels so that they will find out, yes, you've got the translocation for synovial sarcoma. Oh, and by the way, you're HLA-A*02 positive and you've got MAGE-A4 expression. If we can get that earlier, then the relationship between testing and treatment will become less tight. Ultimately that will result in better treatment for the patients and probably earlier treatment for the patients. At the moment, obviously with a new test, this is a new commercial test for MAGE-A4, many of the patients have not yet been tested for MAGE-A4, particularly those outside of the major centers. HLA testing in the major centers has become more of a thing, but I wouldn't say it is ubiquitous even in the major centers. but these therapies that are HLA specific have been known for a while. And so at Memorial, or Moffitt, or MD Anderson, they do routinely test their synovial sarcoma patients for HLA. Okay. Gotcha. And so just based on your feedback from physicians, have there been any, any desire or attempts to treat, you know, earlier patients with TECELRA perhaps, you know, immediately after they receive their first therapy or, as opposed to perhaps the latest line patients initially? Yeah. I think what we're seeing at the moment is a real spread. We are seeing patients, later line patients certainly. We are also seeing patients who have recently finished their chemotherapy, or patients who are actually still being treated with chemotherapy when the intent is to move rapidly onto TECELRA. The label for TECELRA requires that patients have been treated with prior chemotherapy, but that's all it requires. And HLA and MAGE-A4. In terms of prior therapy, that's reasonably broad and I think gives flexibility for physicians within the label to be able to pick the time when this will be most effective for their patients. Early, I think there's a lot of interest in how early is best for these patients. I think that will evolve. Some of that I suspect will require incremental data to understand how to use this. I think we have very entrepreneurial physicians who want to do the right thing, and many of them have talked in sessions about their desire to understand how this could be incorporated in as early as possible. Okay. Then can we talk a little bit about coverage for TECELRA and any roadblocks that you could see, from an insurance perspective? Is it fair to say coverage skews more commercial given the relatively younger patient population? Yeah. Estimate, because really good data on synovial sarcoma is not as easy to find. For sarcomas generally, we estimate on the basis of the data we can get for sarcomas generally that north of 50%, probably 55%, have commercial coverage. Another 20%-25% have Medicare, and the remainder are either DOD, other, et cetera, or Medicaid, teens Medicaid percentage. That's a good mix from the perspective of ensuring the patients are covered. We have policies in place that plans that cover 70% of commercial lives and 77% of Medicare lives already five months after launch, which, you know, for a rare oncology indication where there isn't anything else, that's not unexpected that those levels are high. I think it speaks to the fact that we've not seen any real roadblocks to patients getting the access to TECELRA that they need. Maybe on that point, and a little bit more back on the timeline aspect, I think you mentioned, you know, six plus weeks for apheresis to being dosed. How, what's the timing between a patient sort of being identified by the doctor to going to screening and then going through insurance and then receiving apheresis as an estimate? Yeah. I guess. The testing process, which incidentally can happen and should happen wherever the patient is, not at the ATCs necessarily. That testing process can take a couple of weeks, both HLA and MAGE-A4. It can be done in parallel. It can be done sequentially. We have centralized testing, and we have for these patients, and we have sponsored testing as well for both HLA and MAGE-A4. So there is limited cost burden for that. It is worth pointing out that we do not see anything close to all the HLA tests that get done, because there are lots of other HLA tests that are available and many hospitals have their own approach to HLA testing. They do not need to use ours to understand the HLA of their patients. MAGE-A4, we probably are going to see the majority of patients, but some of the large centers have also, will also bring that testing in-house, at which point we will lose visibility on the MAGE-A4 testing. We will see a subset centrally. That is two weeks. Then, from then to apheresis, depends on the patient need, patient desire. It can be anything from, you know, a few days to a few weeks. Then obviously apheresis through to dosing, estimate six, six plus weeks. The whole thing we are estimating as being, you know, three to four months at this. In the middle there, you have got insurance coverage as well, which, you know, initially, is take, we do not have good data. We have had patients go through very quickly. We have had longer periods. Iovance found that this, they've got more data than us, that they're, that they were taking, I think six to eight weeks initially and they anticipate it come down to two or three. You put all that lot together and you end up with three to four months. Great. So then, you know, just looking forward then into, into the next couple, couple weeks and months, now that you've had this foundation laid with the, the sites up and, you know, the first patient dosed, how should we think about the pace of, you know, patients if, if apheresis and potentially getting dosed over the, the course of the next few months? We will update on the number of aphereses and the number of sites that we have open, although the number of sites is available on tecelra.com. The number of aphereses we'll update at our earnings call in March, and that will be aphereses from the beginning of the year through to that point in time. I think, oh, I don't want to say anything in advance of that other than, things are tracking very much to plan. Perfect. With our last few minutes, I wanna touch on lete-cel. You have committed to submitting a BLA this year. What are the gating factors for those regulatory discussions? Any potential to, you know, accelerate timelines given your experience with TECELRA? Yes. I think the timelines that we've built in for lete-cel very much reflect our experience with TECELRA, and although the manufacturing process is different, this is a very similar product and we anticipate that what we need to demonstrate for the agency will be in the BLA will be very similar to what we demonstrated with TECELRA. We feel quite confident about those timelines. We anticipate taking the same approach that we took with TECELRA, which is a rolling BLA initiating tail end of this year with the clinical and preclinical modules, then mod three, the CMC module, in the second quarter of next year. We were successful at getting breakthrough designation for MRCLS earlier this year. That goes together with the breakthrough designation we previously had for synovial sarcoma for lete-cel. We anticipate an eight month cycle review, six months from filing through to approval. We feel good about those timetable. I think our view is we know what this takes, and we know what this takes in terms of data and we know what this takes in terms of time. Great. Can you remind us the, sort of market opportunity, you know, what degree of overlap, first of all, is there between TECELRA and lete-cel in synovial sarcoma? And then with MRCLS, how are you thinking about the peak sales potential? In synovial sarcoma, the MAGE-A4 and NY-ESO-1 are both expressed, between 60% and 70% levels. That's what all the data suggests. And as far as we can work out, they're not dependent variables. They're independent. So there's a large overlapping population. That's why for our sales for lete-cel, we've only assumed that we can address the incremental patients who are NY-ESO-1 positive and MAGE-A4 negative. Now, obviously there might be some patients where they're double positive and it makes more sense to give NY-ESO-1 targeting because it's massively more expressed or for some other reason. We are sort of agnostic to that. We think that the patient should get whichever cell therapy, they should get a cell therapy, if they're eligible, but they should get whichever cell therapy they, them and their physician determines is right. We are making both of those available. There is the opportunity for some of those patients maybe in the future to be dosed sequentially. We have got anecdotal evidence of patients receiving two cell therapies targeting NY-ESO-1 and MAGE with some levels of success. I think for our starting position for the peak year sales forecast for the sarcoma franchise in the US of $400 million, we have basically only assumed the incremental patients. The MRCLS is slightly different because that is only lete-cel. Actually, NY-ESO-1 is expressed in a very high percentage of MRCLS patients. The publications will say it is 95% or so. In our clinical trial, in the IGNITE-ESO trial, every MRCLS patient tested for NY-ESO-1 was positive in that first cohort. It is very high. That means the slightly more patients will be, have the, have the target expression. They're obviously still HLA restricted. Overall, we anticipate the addressable patient population, dual positive population for TECELRA is 400 patients. The dual positive population for lete-cel is about 600 patients incrementally for a total of about 1,000 patients. The only thing I'll add to all of that is it's worth knowing fundamental to our case is that this goes through the same commercial channels. These are the same physicians, this is the same field force, these are the same systems, patient support networks, et cetera. There's a lot of synergy in establishing this franchise. Great. Yeah, with that, I think we're up on our time, but obviously a lot to look forward to in terms of the commercial progress as well as regulatory for lete-cel. I wanna thank you again, Adrian, for joining us. Thanks, Paul. Appreciate it. Thank you.