Good. Thanks for joining us on Day 1. My name is Daina Graybosch. I'm an analyst here at Leerink Partners. My team and I cover immuno-oncology, and we're really excited to host the management team from 2seventy, Chip, Anna, and Vicki. So we have about a half an hour, and we're gonna jump right in because there's actually a lot to discuss. Discuss. I'm excited to do so. Okay, so let's start with the ODAC meeting. We don't, as of now, I don't think, have briefing documents, which should come today. But prior to the briefing documents, you know, starting, I'd say, you know, last year when you presented the KarMMa-3 data at ASH, both you and BMS management have sounded quite optimistic about the outcomes for Abecma at the ODAC, and I wonder if you could outline what underlies your confidence. Yeah, Daina, it's a good question, and just start by saying thank you for having us to your conference here in Miami, and pleased to be here today. You're right. We, I think, feel very good heading into Friday's ODAC. That starts with the strength of the KarMMa-3 data. As you know, the study was stopped early for strong efficacy at a planned interim analysis on the primary endpoint, which was progression-free survival. And that's a really important outcome in this patient population, triple-class-exposed patients with an aggressive form of the disease in need of better treatment options. And so what we saw on that primary endpoint was profound efficacy, and we stopped the study early. Beyond the efficacy signal we saw there, we also looked at overall survival, and we'll get into that. That's, we know, gonna be a key discussion topic on Friday. That secondary endpoint was confounded by the ethical and we think patient-friendly study design with the crossover. But even looking at those data when adjusting for crossover, the analysis favors Abecma. We have a safety profile that is consistent and we think supports the benefit risk. And lastly, we've had the same discussion with regulators in Japan and in Europe and with a successful outcome. So, our team has been hard at work and we feel very good heading into Friday, but certainly leaving nothing to chance. At the last CAR-T ODAC, I looked through every single one. Well, there's not that many because CAR-T hasn't been around that long. Was for the first CAR-T approval, Kymriah, in 2017. They had a wide array of topics. It was risk mitigation, patient monitoring, safety, efficacy, CMC. So it—you know, as the first one approved. Right. That wasn't surprising. What do you think was about KarMMa-3 and CARTITUDE-4? Because we haven't said yet, but there's two parts to the ODAC with your competitor, J&J, and Legend going first in the morning. What about those two trials spurred this as a next ODAC topic? Yeah, I mean, I'll just comment. It's interesting. It's been seven years. Didn't realize it was that long since the last CAR-T ODAC, so I guess that puts us in a rarefied club there. You know, I think the FDA has been focused on overall survival, not just with CAR-Ts, but more as a general focus topic. And so I think certainly not unique to our product or to our competitor's product, but something broadly that they've been focused on. But... And I know you have thoughts there as well. Yeah, so overall, I do think that it is, our Abecma KarMMa-3 study was the first randomized phase three trial in multiple myeloma, and there are some aspects that are important to consider, especially now, where the focus will be overall survival. And I'd like to highlight again, that KarMMa-3 and CARTITUDE-4, while they are discussed the same day and probably both will have overall survival as the main topic, I'd like to kind of clearly also mention again that KarMMa-3 is a different study. It's a different study population. It's a patient population that is triple-class exposed, so have seen all commonly used classes of therapy, such as proteasome inhibitors, IMiDs, as well as anti-CD38, as well as refractory to the last line of therapy. So it's a heavily pretreated population, while though earlier in the treatment course, 2-4 prior lines. It is important to keep that in mind when interpreting the results or the discussions on Friday. However, we feel, as Chip already mentioned, we feel very confident on the discussion and look forward to Friday. How do you think? Why, why should we keep that in mind? Specifically, what should we be looking for based on that? I do think it's more like, since both will be discussed on the same day, it is important to consider there are some commonalities- Mm-hmm. because both are randomized phase 3 trials for CAR-Ts in myeloma. But again, it's not not everything is the same, so that's kind of important to keep in mind. As we're listening to the discussion in the morning, remember that those are the differences in the afternoon. Yeah. Different patient populations, and I think it's easy to compare across because that's what people do, and I think it's really important to just recognize that, which I know you do. But broadly, I think that's a key theme as we compare these data sets, and we certainly will have different cuts of those data sets, cuts that the sponsors have done, cuts that FDA have done. And as we inevitably, it's—I think it's a human thing to compare, but it's we believe really important to keep that in mind in terms of the different populations studied. Other than the population studies studied, I mean, so far, everything looks almost identical from FDA perspective. We don't have a lot of information. Do you, do you believe the conversations will be generally similar? I think it's. I don't want to over-speculate. I think it'll start with a focus on overall survival, but you know, certainly because of differences between the products, differences between the patient populations, differences in study design, crossover versus not, for instance. You know, the conversations I think will naturally take different paths. But you know, I would say our team is focused in on our story, our briefing book, our data set, while you know, certainly listen to what happens in the morning. I think our team is pretty locked in on the story we have to tell. CBER, seemingly, looking at the last ODAC, led the FDA discussion, so it was CBER employees doing the FDA presentations. We understand Friday will be more led by CDER. Does that matter? I don't think so. I think that's just who's sort of in charge of the review of these products now. We talked about it internally. I don't know if Mike had a different view there, but I think it's more administrative. We didn't see a... Unless you knew of something hidden behind the trapdoor there, we didn't know that there should be a different flavor or approach from before. Investors think that the leadership of those two organizations have different sort of focus, priorities, risk tolerance, and that that may filter down- Okay to their organizations, I think is where the question comes from. Yeah. Yeah. You know, I think it's hard to say, and again, we've gotten this question before, well, why have an ODAC? You know, sometimes the FDA wants actual advice on the review and on the process. Sometimes it's an opportunity to sort of set a new bar or, you know, kind of deliver informal guidance to more broadly to the industry. So lots of different reasons for an ODAC, and, you know, tough for us to say. But again, we feel good and then... Okay, last one, and then we'll move on, but it's quite important. How do you envision the risk-benefit calculus yourself for BCMA CAR T to evolve as these products move into earlier lines? So today, we're talking about, you know, moving into the third line or for a competitor product, second line, but you're gonna go even earlier. So what do you think should be the risk-benefit, and how should physicians and regulators be thinking about that? Yeah, no, it's, it's a great question. It's one, we're excited about because I think as you move into these earlier lines, the... Look, you have to have the efficacy profile to, to be competitive, to be relevant, and I, I, I think, we do, and, and we're really excited to, to share that, on the other side of ODAC, on the other side of a PDUFA action. But also, the safety profile, becomes, more and more important, and, side effects that may happen at a, you know, high single-digit rate, in a late-line setting when all other options have been exhausted, you know, may be calculated one way in terms of benefit-risk. As you move earlier, those, those, safety liabilities, and side effect profile becomes increasingly important. We think that's gonna be important in a commercial setting in third line. We think it's gonna be even more important as... And as you know, we're in the KarMMa-9 study, which is a newly diagnosed multiple myeloma study that got underway last year. So, again, we believe very much this is gonna play out over a number of years, but certainly, the safety profile will matter more. Okay, let's move on to commercial. So post-ODAC, probably the number one question I get is a simple one. So they're gonna. Let's say Abecma grows this year. How sustainable is that growth, following the initial bolus? You know, it's a good question. I don't. Unlike the fifth-line plus launch that we had, a couple of years ago, we don't see this as much of a bolus opportunity. It is a big opportunity. It's, you know, today, roughly 4,000 patients on label, on approval based on the label we are thinking about, and, you know, certain patients we studied, that's several times larger. And, you know, is it 16,000-18,000 in that range? A much bigger patient population. And so, you know, again, there's not enough capacity between us, between our competition to get to those patients, in the near term. And again, we think we have a efficacy profile and a safety profile that we think can be competitive. We know there are other products that are coming along behind us, they at this conference, and that's exciting for patients, too. We think they are likely gonna have to start in the same fifth-line plus setting and work their way up. So again, our belief is myeloma has never been winner take all. And so, you know, we plan to compete, BMS plans to compete for those patients. Yeah, I'll stop there, but... A big competitor in this space, I'll just say Kite, has put out a number of, like, a capacity they can be at mid-decade of 24,000. For all CAR T? For all CAR-T- Yeah out of CAR-T Yep. How do you think the other big companies are tracking? Is everybody tracking towards that kind of similar number? Like, how much actual capacity for lymphoma, myeloma, and now, of course, we're moving to other things like autoimmune Yep or solid tumors, but do you have an anchor? Well, you know, we've heard J&J Legend talk about, you know, 10,000 patients of capacity, maybe more. So no, I think that that is going to be the new standard, and certainly, you know, together with BMS, we have a facility in Summit, New Jersey, which is Abecma and Breyanzi. We have a second site up in Massachusetts and a third one over in Europe that are coming online soon. So, you know, I think BMS has been less specific about, well, it's exactly this number that we're going to have by exactly this date. Prefer to keep that a little closer to the vest, but it's, it's, it's in those ranges, and I think what it teaches you, too, is that if you want to compete and win in CAR T space, you know, treating a couple hundred patients does not give you the economies of scale to really be there. And so our belief is this sorts in a way where there's sort of a, you know, a number of large competitors that have the economies of scale to really make a business of it. What is the number of how many doses you think are required to be economies of scale high enough to be profitable? And do you count doses across, so you could account Abecma and Breyanzi doses together in the economies of scale? That's probably a better question for BMS. Okay. What I can say, and we can get into this on some of the financial questions, but the number of patients we need to treat from a 2seventy perspective to break even is much lower than those kinds of, you know, tens of thousands of numbers. Much, much, much lower, and you know, that's... Again, when we announced the Regeneron asset purchase last month, that's part of the impetus is that it gets us to a place where we can be a profitable business on in very achievable numbers. 500 doses a year? More than that, and we're, we certainly have ambitions to treat a lot more patients than that. But certainly numbers, you know, if you look at the first quarter of last year, we did $118 million of U.S. revenue. Under the new cost structure, kind of when we get to steady state there, that can be enough to achieve break even. Got it. Okay, let's go back to commercial for a second and move away from manufacturing. So assume that in the future, there's a future where J&J could supply all the third to fifth-line demand in any site that you have overlapping with them, so BMS, J&J sites. What do you think is the baseline of Abecma share, and what kind of patient is getting Abecma in that situation? So today, it's 25-75 and 2/3-1/3. You know, it's depending on where you look, depending on which site you're talking about, it's definitely not one size fits all. Like, there are even within a site, if they have two CAR, you know, both CAR- Ts, are they an active user of T-cell engagers or not? But also within those sites, what's their experience with the product been? How long have they been using it? Have they had a case of neurotox, a case of Parkinsonism that is irreversible? Those things matter and can affect treatment patterns, and we've even seen in instances where a site was more tilted towards the other product, and then you have a serious safety event that it can tilt back the other way. So we view it as more fluid, not static. And again, I think if you do the math, and you say: Geez, we're at a comparable share in the third line, that's a whole lot of growth from where we sit today. So when we talk about getting it back and back on growth, that size, that opportunity, our ability to compete in those sites and have. You know, we don't have to have the dominant share, but we have to be relevant. To your last question, I think we compete for all patients, so we do not think about the product as, oh, just segment for these kinds of patients or, you know, this subset. We don't expect that in the label. We certainly don't guide that way from a medical affairs perspective, commercial perspective. So we've talked about the neurotoxicity. You've mentioned it a couple of times. So what do you, do you think mechanistically underlies, CAR-T neurotoxicity, BCMA? I mean, we've seen it with CD19, CD20 CAR-Ts as well. And why are there lower rates observed with Abecma? Anna, do you want to Yes. Speak to that? Thank you, Daina. So when you look at the general term, neurotoxicity, there is a lot of confusion, and there is, like, this general term that is coded by CTCAE. That's the traditional coding of any adverse event. Neurotoxicity is a very broad term. However, when we go closer into the CAR-T-associated neurotoxicity, such as called ICANS, then it is becoming evident, of course, that CAR-T-cell therapies have these transitional neurotoxicity events after infusion, and in the case of Abecma, with early onset and early resolution, as well. And going further than that, there also have been reports on the Parkinsonism, Guillain-Barré syndrome, et cetera, and these are a bit more unique, also more unique to other products, and we haven't seen those events as much in with Abecma, so it's really, really low numbers in the thousands of patients treated so far. And so that, that's a bit of a different neurotoxicity signal that is not necessarily a class effect, but more specific to products. Have you seen, I think, the lower grade, like cerebral nerve palsies with Abecma? So again, we have very, very low numbers of those, like Parkinsonism in single digit number, not, not even, not, not percent numbers, cases. And so we have one case in our USPI, and, and, and that this is it. So we do not have, in our clinical trials or anything. Also, specifically KarMMa-3 in the early line setting, we didn't have anything in that direction. Yeah. Do you think those are related? So the cranial nerve palsies, is that a low grade of the Parkinsonism, or are we—those different things? Since we haven't observed many of those cases or haven't observed particularly those cases, I think it's hard for me to comment on this. There may be an association, and probably the mechanism may be similar or the same, but I don't think that I am the right one to comment. So there's a thesis out there amongst investors that Arcellx and Kite has a product, coming up next, or there's a couple coming next, but one of the ones called anito-cel. And the thesis is it's gonna have similar efficacy as Carvykti and similar safety as Abecma, and Kite make a lot of it. If that's true, where do you see Abecma's place in the market? Yeah, I mean, so I think if that's true, that's something still to be proven. And again, I think understanding exactly what patients were treated and kind of what their disease progression was, and I think all of that will matter as we get into bigger studies, as we get into real-world evidence. We've even seen it with products that are already on the market today. Our efficacy in the clinical trial versus efficacy in the real-world evidence. Very consistent. That is not always the case. And so, again, I think this will play out over time. I would note, you know, other competitors are gonna be coming in in a later line setting, looking to move forward. That's tricky, and the comparisons that you have to do, the studies that you have to run, it just... Not to say that it can't be done, but it's tricky. And, you know, certainly, the manufacturing prowess that Kite's built over, you know, being one of the pioneers here is certainly very impressive. You know, our sense and our experience is you still have to go through those steps. Step ups, that it's not out of the gate, this massive capacity, and there is a learning curve. We observe with every sponsor that you have to go through, and that's sponsor-specific, it's product-specific. We certainly... You know, it's one of the ones we're watching closely. It's great for patients, and, you know, again, this is a large market, so we don't believe it's winner take all. We believe it'll be, you know, it could be an important treatment alternative when it gets there. Let's talk about KarMMa-9 for newly diagnosed multiple myeloma. Yeah with suboptimal response to transplant. A question we get is, "Why do you believe transplant will remain the standard of care? That will be a relevant indication. Yeah, I mean, it's been there for such a long time, and it is, it's a very effective therapy. So to dislodge it completely, you know, is, I, you know, never say never, but I think that's a tall bar, and that's one that a lot of other products and other companies have had challenges, you know, getting there on. But that's a tough study to believe, even if you have successful data there. Those are treatment patterns that have been in place for a long time. Anna, I know you from a clinical perspective may have thoughts. Yes. So thanks, thanks, Chip. Transplant has been the standard of care for a long time, and so far, many studies that have tried to beat transplant haven't been successful. So it's a high bar to reach. And again, there are patients that are specifically really, the unmet need, from the get-go, and I think that's also a patient population you're targeting for KarMMa-9. And the patients who have a suboptimal response post-transplant, they really have a high unmet need, and therefore, we believe the addition of Abecma can add a lot of value to those patients. Also, we have seen the updated data at ASH from the KarMMa-2 cohort 2C study. It's a phase II study that looked exactly the patient population, patients who haven't achieved a very good partial response post-transplant. We have seen a complete response rate in these patients of near to 80%. Also, what was very encouraging is patients who received lenalidomide maintenance post-Abecma in this study didn't relapse at a median follow-up of 14 months. So it's really encouraging to see, and that gives us a lot of confidence that we will have a successful KarMMa-9 study. KarMMa-9 allows len or requires len maintenance as well? Yes, correct. Allow or require? Require to keep bias as well as keep heterogeneity low. Interesting. Let's talk about expansion of delivery of CAR-T in the U.S. So ATCs, Authorized Treatment Centers. When we look at it, we think that ATC expansion is—could be an exercise of diminishing returns on investment. Do you agree? And, how... Or not. And, how is BMS investing in a cost-efficient manner? I'm presuming some of that investment goes back to Abecma profitability. No, it does. You know, I think the rationale to do that is simply to... You know, the U.S. is a big place, and, you know, while these started in academic centers of excellence, this is becoming a modality that is, you know, increasingly mainstream. And one that if you want to get to those tens of thousands of numbers, you're going to need to have a broader footprint than 40 or 50 centers. So I think that's part of the rationale. You know, the other is for sicker patients who live in remote regions; it can be a barrier to treatment to say, well, it's a, you know, it's an 8-hour drive to the nearest treatment center, so that factors in as well. We certainly look at all aspects of the P&L in terms of profitability and return on investment. You know, that's balanced with the, I think the, with the patient mission and, you know, if you can impact another patient life and give them a chance at more time, that's, you know, we think those things will sort over time, right? And, again, when we look at our numbers, and we may get into it here, it doesn't take a lot for us to get to a profitable place as a company, which is great. Let me end with a couple COGS questions or manufacturing questions. We, you know, using your P&L and what you report, you can estimate. It's not perfect. You don't give us everything, but we would guess or estimate an Abecma COGS in 3Q last year at above $300,000, and that was part of the driver of negative gross profit. But then in the fourth quarter, sales revenue actually shrunk, but you had a positive top line on gross margin. Wondering what actually is driving the difference in a COGS or gross margin quarter to quarter, and we think about that going forward. I'll ask Vicki to comment on that one. Thanks. Yeah, thanks for the question, Daina. Great, great point. We've, we've experienced lumpiness over the past two years, actually. Yeah With COGS, and we do actually think it's trending favorably. What you saw in the third quarter there was, there were some one-timers. It gets lumpy when you consider batch write-off frequency, or you consider sales volume. Obviously, the first half of 2023 looked very different than the second half of 2023 from a volume perspective, so our fixed cost base was spread over fewer slots. But again, we do see this trending favorably. I think, we've come a long way since the first quarter of 2022, and even the second quarter of 2021, our first quarter of launch, and so we're excited to continue to invest with BMS in making margins grow. Is batch write-off like a vector batch? Yep. Okay. And that could... Is it analogous to the COVID vaccines in this case? Like there was over-vector manufacturing that had to be written off, or we just sometimes It just. Batch gets written off? Yeah, more within the spec. And again, that's those can take a long time. There's a lot of factors that play into that, but that's more of a spec, and as to Vicki's point, that can be lumpy 'cause each batch can treat a bunch of patients. Yeah. Within the drug product side, which is, you know, I think more about our ability to deliver in a commercial setting, that write-off or that in spec rate is still quite high, north of 90%. Can gross profit get to north of 80%, north of 90%, and what would it take? It's a goal. Yeah, I would just say it's a goal. I think we're making steady progress. There's a couple of things on the horizon for us, including the introduction of suspension lentiviral vector, and hopefully increased volumes with a potential increase in our addressable market, as Chip touched on earlier. So we're hopeful that with a few of those factors and increased focus on operational excellence by the great BMS team down in Summit, that we will eventually get there, but certainly there are steps to take from here.