Okay, great. Let's go ahead and get started. Welcome, everyone. This is the Fireside Chat with 2seventy bio. My name is Vikram Purohit. I'm one of the biotech analysts with Morgan Stanley Research. Before we get started, I need to read a brief disclosure statement. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, I'm very happy to have with me Nick, Chip, and Steve from the 2seventy bio team. Thanks for joining us. Appreciate your time. Thank you for having us. Of course. I thought maybe the best place to start, Nick, would just be to recap some of the recent news you've issued around the restructuring of the business, the prioritization of the early-stage pipeline, and then we can go into specifics from there. I'll turn it over to you. Appreciate that. Thanks for having us, and I know there's a lot of news going on with a lot of different companies, so I think it's a little hard to keep track of. But yesterday, we did announce an overall restructuring in the business for a couple reasons. One was to make sure that we could rebalance the company to sort of run at the mission in the most effective long-term manner. And really, as we'll get into it, some of the, what we think sort of near-term transient wobble with Abecma is an important part of our business and how we fund our business. At the same time, when we look at our programs, how do we make sure that we can effectively pursue the ones in the clinic and after that? But we need to do it in a more cost-effective way. And so what we did, we basically, shifted to what we are calling more of a collaborative-based R&D model. So Abecma is largely untouched. Every contribution that we have to that and so forth is, is untouched. What we unfortunately had to do was right-size, the middle part of our company, if you will, to make sure that we can sort of, trim the overall R&D spend, but at the same time, launch into and continue to support the clinical programs, more cost-effective way. At the same time, expand our relationship with JW in China, who we've been super impressed with, that's worked with us on one of the solid tumor programs, and put a few of our programs in their hands in a collaborative-based model that allows us to pursue those through proof of concept and then see where we go. So it's a, I think it got us to a pretty creative and I think cost-effective way to run after our pipeline that reflects the times. Right now, it is, it's just bouncy all around in the macro environment and in the case of a micro, so we felt the need to do it. But I'll just say it's not easy. It's always hard. We have 155 folks at the company that are just magnificent, great human beings that have done amazing work, that we have to say goodbye to. So that, yesterday was not pleasant, but at the same time, it's, it's the right decision, for the business. Got it. And, before we get into specifics on Abecma and specifics on, certain pipeline programs, what is the scope of the pipeline prioritization? How are efforts with the non-Abecma assets going to change going forward, and how are the thresholds for moving those programs going to change going forward? Yeah. And some of this is hard to necessarily interpret on the outside, but internally, it's fairly dramatic. In one sense, we're taking some of the programs like our 369 program, our AML program, and those are very just heavily gated. So any at-risk spend is the ones we're saying has to be predicated on pretty strong, high bar, clinical proof of concept, right? So that allows us to think about future dollars a little differently. That's one. There are some programs that are barely visible to the outside world that have been paused, like next gen AML, until we see things play out. And then programs that were slated to be operated on the inside, in the case of one additional solid tumor program, as well as an effort that we're initiating in the autoimmune space. Those have both been now done and now in collaboration with JW. So that, that is sort of stretching out and executing. What we didn't want to do was just stop programs. Like, was there a more creative way? And thank goodness, we have this fabulous relationship with Regeneron. And the last year, working with JW, we've seen they're doing things faster and cheaper than we had anticipated, and so we're leaning into that relationship with James and team and been super pleased. So this is that, I'd say, almost third-generation model that we're working on. So that, that's the extent, and that translates into now a runway that gets us into 2026+. And the reason I want to say plus is because we're still working through when you rightsize a company like this, there's lots of things you can't do overnight. This is everything from real estate to rent and those types of things. Right. And so we're working through that, but at the same time, super fired up about... And it's a little hard to say because it sounds insensitive based on the changes, but looking forward, very excited about the mission and continued mission based on what we think is highly differentiated science. Got it. Okay, that's, that's super helpful. Thanks for that. Maybe with that, we can talk about Abecma. Maybe two questions just to kind of set the stage so everyone's in the same spot with their understanding of what the trajectory of Abecma has been throughout the year. So with 2Q, there was some debate and concern around how the product is doing, what the impact of competition was and could be, so how and also manufacturing. So maybe unpack all of that for us to explain what happened with 2Q results and how those different factors are going to be playing out throughout the course of the year. Yeah. Let me, let me say a few comments, and then I think, Chip, we've been going through this run all day long, right? So we'll, we'll do a little, like, Geoff dance up here. But I'll zoom out for a second and say... And this is obviously our opinion, our belief, right? And, and we need to bring along others through execution. But I think there's just been this incredibly sort of exaggerated response to the dynamic in an emerging field. The reality is, it's complicated. The reality is there's a bunch of different puts and takes that are going on in a moment in time that may or may not be reflective of how it ultimately settles into the practice of medicine. And, and that's not a vague statement. That is a very strong belief that Carvykti is an amazing drug, Abecma is an amazing drug, and so is the T-cell engagers, et cetera, and they're all going to settle to help the myeloma community. There are still way more patients that are addressable that are not yet being treated... So this idea that there's a winner takes all is actually, I think, just appalling, and actually is not in the interest of the myeloma community. And there are words being thrown around here that I think are almost insensitive and irresponsible as it relates to that, and I'm happy offline to tell you more about how I feel about that. But it's had me make a few laps around the block, so I don't get too crazy up here because it is really, it's insensitive, and it's also, I don't think, accurate, which is Abecma is an amazing medicine. There's a moment in time here, Chip will walk through, where I think it is a tough dynamic to figure out how to understand how these things are moving. That does not mean that there's a demand problem. It does not mean that Abecma is not a good drug. It does not mean that Abecma will not be in a competitive share situation with Carvykti as we both march upstream. That can be a very healthy process for everyone, especially for the myeloma community, where there are, like, literally tens and tens of thousands of patients going untreated today. So with that as context, as politely as I can say it, I'll let Chip sort of bring us home on some of those variables. Sure. Yeah, sure. So, you know, second quarter actually was still a good quarter for us. I think we were up to flat for the first quarter and over $230 million of sales for the first six months of the year. I think the reaction was more the commentary from on the BMS earnings call; the third quarter was expected to be a down quarter, followed by a return to growth. And so there's been a lot of consternation and what and why, and how is that happening? And I think that, you know, there's an evolving competitive dynamic in the marketplace. I think we have, for more than a year, been in a stance of having, as we've said, a line out the door, at the sites where we're operational. Training physicians were trained accordingly, that, you know, when they had patients and finding out you can get a slot, but it's going to be 3-4 months before we can manufacture for that patient, because of the backlog, an off-the-shelf T-cell engager looks attractive. And so, if I ask for 10 slots, I get 2 slots. That kind of dynamic, that's abating. And I think one of the key challenges and key priorities is training doctors on that change, that if you want a slot, like we're, you know, going to be able to deliver one much more rapidly. Still, you know, high in-spec rates, still a very quick turnaround time. T-cell engagers, I think an important part of the treatment paradigm. I think we're out there, though, very importantly from a message perspective, is that outcomes on a CAR-T are better if you take a CAR-T before a T-cell engager. So that sequencing message and that sequencing data is a really important educational opportunity here in the second half. And then with regard to the other competitive CAR-T in the space, as Nick said, it's a great product as well, but there's a lot that's not understood broadly, particularly with regard to real-world evidence, particularly in the important differences of both in the safety profile, but how convergent some of the efficacy data are and how that may evolve over time. So, this is a top priority at BMS. There's a very expanded commercial effort. All of that is going to take time to show, and I think we're still in the early days of that. And again, from our view, you know, 2023 will be a growth year for us on an annual basis. But what we're really excited about, and what we will show over time, is that 2024, with the third-line label approval, expected approval, PDUFA date in December, we expand into a much larger market, going from roughly 4,000 patients on label today to roughly 16,000 patients on label in the first part of next year. And so we are very focused on that PDUFA date. We're very focused on expanding manufacturing to be ready for that, and at the same time, there's myriad commercial opportunities that I think we're still, to be candid, early days on. So what you're hearing is Q4 growth rate as a kinetic into 2024 is our focus. You're also hearing that there's not a demand issue. It wasn't a manufacturing issue. It was sort of a funky dynamic in the space that we think will work itself out in a more natural way as this field settles. We got to go prove it, and that's certainly the engagement we are doing, and BMS very strongly believes in it, and it's certainly not in the interest of our competitor to sort of highlight some of those things, but that's okay. It'll just have to play out quarter- by- quarter. Got it. Okay. So if I understood you correctly, and please correct me if I'm wrong, for 2Q, the impact of competition that you and Bristol Myers have, have cited, it's more competition from the bispecific, just due to the inability for manufacturing supply to keep up with demand for those few months? Yeah, for a period of time- It's more that dynamic- Came on middle of last year. Right. But that off-the-shelf option and innovative therapy- At that point. ... in very late line setting, was important and attractive, particularly when the supply and demand was so imbalanced. Yes. Got it. So that balance, right, is what also now say, "Okay, we're going to do that." Well, one of the things that BMS is certainly doing is they're leaning heavily into the continued expansion. There are plenty of sites where you can only get Abecma, and also getting more boots on the ground to have this dialogue and engagement, because now it is about what's the right way to use these medicines? What is the real-world data telling us, et cetera? That takes a while to get itself into not only the sort of the major centers, but also the centers that are referring. And that takes a little while for that to get in and settle in a way where the data has to settle in the best interest of patients, and that's not necessarily what we have been seeing. And so that's one that is on the come, and certainly Wall Street is saying: "We don't believe you just yet," and that's okay. I think one question, going back to the 2Q, I mean, related to what you just mentioned: Where did the competition really come from? And I'm, it may not be a very straightforward answer, and it may not be a one-word answer. Mm-hmm ... but in general, was it more from your perspective?... the dynamic you kind of outlined of bispecific spillover, supply shortfall at that moment, or was it kind of head-to-head competition versus- It's both. Both. It has to be both, right? But at the same time, they're in a launch kinetic, right? To fill your centers when you don't have that many centers is sort of not that big of a deal. Mm-hmm. Right? We're way more centers, and then you're dealing with this bolus situation, and then you get into the, there was a lack of education, saying, "No, actually, there is availability, there is slot," as we grow it. So it's those dynamics, at least as we're seeing. Are we 100% right now, right? Are we probably closer somewhere in the middle between all of us? Sure. So I think I don't want to sit here and say that there aren't instances, 'cause there are, where there are centers saying, "Hey, we're using Carvykti, not Abecma." There are also instances, and we know plenty of them, where there's actually, "No, we're using Abecma over Breyanzi because of different profiles of patients and providers have different perspectives." So all that, that whole settling is all happening, and that's where everyone loves to jump to conclusions, and I think we're clearly, we believe, in that moment, and we've just got to kind of grind it out and keep working at it. And that's. BMS feels the same way. They, they sort of feel bad for us 'cause we have to sit up here and talk about it. They don't, right? And Chris and Lynelle and Giovanni and all those guys are, I'd say, super committed to their cell therapy franchise. I think you'll hear more on their R&D day tomorrow and so forth. Can't speak for them, of course, but we're super pleased with their commitment, and this bump is not pleasant, especially for us, but it's led in a weird way. I like to say, "One door closes, two opens up," to a pretty creative, I'd say, better model for 2seventy. Putting aside the emotional and human side of this change that we just went through. So we're gonna run it back, we're gonna run hard and believe. Got it. Got it. That's helpful. On the topic of BMS's commitment to the, to the franchise, you mentioned, with your 2Q update, strengthening the commercial presence behind the Abecma. Mm-hmm. So I wanted to clarify a couple of things there. Is that going to happen, post the potential third line approval, or is that something that's underway now and is going to be happening before then? It's been underway. Okay. Right? It takes a while. So that is increasing the number of boots on the ground, having the conversations with the real world data, with the sequencing conversations, et cetera, getting out to the centers, senior leadership on down, across the board. All those things are happening. So, and the other one is the expansion of the sites, right? So starting new sites, now, as you can sort of prepare for and lean into, you can't wait till, you know, you get into that third line, and say, "Oh, wait a minute, now I should expand sites." Right? So we're continuing to lead that expansion, and considerably more sites and Carvykti is available too. But I, and again, I know I almost hesitate to say it 'cause I'm so irritated by some of the conversations I'm hearing, but it is not a, it's a co-opetition, right? It is in the interest of a center to have access to both, so they can treat as many patients as possible with myeloma. And that statement I'm gonna stick with because I believe it, and I think that's the way the market will ultimately settle as you start to understand the differences between these medicines, the differences with engagers, and you can mention all the newcomers as well. It's all gonna flow into the system. And then look forward to a frontline study that starts to look at suboptimal response to transplant, right? That's we think is a real need, and we know and seeing some of the early data on how Abecma performs there, it's pretty outstanding, with a pretty amazing cell safety profile. Understood. Is there any color available at this point on what the size of that increased commercial presence could look like? Yeah. Giovanni and Chris would probably tackle me off the stage. So why—I think you should ask them the question. Okay. It's sizable, and they take it seriously, and they're highly levered because they also have Breyanzi. They have other assets that are sort of coming towards the commercial space. You know, I'll let them reference that. So we're excited about the breadth of their cell therapy platform and their commitment to it. If it was just us in there, right, then they could easily write it off, right? That's at least not my understanding, and, but I think that's a... At this point, it's a really good question for Chris. So, go ahead and hit him with that tomorrow. A historical myeloma presence, which was- Yes, of course. ... was part of the- Launch collaboration, background with Celgene. Right. Okay. Maybe I'll ask you another question that maybe might be a little bit easier for you to answer. I guess in terms of, To avoid this question, is that what you're saying? Maybe we can talk about what are some of the key messages that this increased commercial footprint is going to be emphasizing to centers when kind of trying to make the second push behind the Abecma? What are the key talking points? Slots are available. 90+% in-spec rate, right? You order this drug, you get this drug, right? Then it's also sort of the appropriate sequencing, engaging. How do you like to treat your patients? What are the different types of patients? Let's have that dialogue, right? And then, so that's a T-cell engager conversation. Not at the expense of, but it's in addition to, just to be clear, I actually think there's just a sequence that makes probably more sense than not. And then there is a. Let's talk about the real-world data experience and the true difference between Abecma and Carvykti and what makes the most sense for you. Right? Those are 1, 2, 3, 4s. They're pretty straightforward, and there's a lot of wood to chop in there. Mm-hmm. They're pretty talented at what they do. So, but it takes a little bit of time, right? So that's where we're at. And there's plenty of centers where you're having that conversation alone, right? Meaning, we're the only ones in that center. So, but I'm not under any kind of, what I'd say, illusion or disillusion that this is gonna happen overnight. Part of the reason that Chip was pretty forceful in his role to say: We need to make sure we have the time for this to settle in, right. So let's make sure we have a company and a runway that can do just that. And that's what led to, in part, this big decision, saying, if we get that runway into 2026+, this will all settle well before that. But at the same time, how do we do that and still drive at the innovation that we feel so strongly on behalf of our mission and patients? Understood. Okay. That's helpful. Maybe we can just take a step back and talk a little bit about patient numbers. Just to kind of clarify the setup going into a potential third line- Yep. Approval. So what is the addressable population for the current label for Abecma, and how does it increase with the potential label expansion? Yeah, so today, fifth line + is our, our, approved label, and that's, you know, we estimate roughly 4,000 patients on that label in the U.S. today. Based on the KarMMa-3 data- Yep and, December PDUFA date, that is, is still on track, that would expand us into a U.S. patient population of, we estimate, about 16,000 patients. So roughly fourfold larger, you know, again, which is driving the investment and continued manufacturing expansion. So, you know, all- But just Legend, it's twice those numbers. So yeah, there- You can figure out where the truth sits in there. Somewhere in the middle. Yeah, yeah, who knows? Whatever we say, it's double. So it's all good. But, you know, whatever that is, it's meaningfully larger than we are today. And so I think that whatever dynamics that we're in right now, I think there's... you kind of turn the page and very much it is a new, a new environment. Got it. Okay. The 4k to roughly 16k with- Yeah The label expansion. And based on the market research you've done, I'd be curious to hear your perspective on how the, the ramp, the uptake in earlier lines of treatment with BCMA CAR T could differ versus what we've seen in late line. Yeah, this is a very important question, right? Because one could say, is this gonna get relegated, and does that logic hold water? And I think that's probably best answered by Steve, our Chief Medical Officer, who's actually treated patients for longer than he's been in industry. So Steve, maybe comment a little bit on your views on that. Yeah, I think, you know, there are some basic principles of oncology treatment. The first is, you wanna use your most effective therapy as early in the treatment course as you can. And the second is, particularly for a disease like myeloma, which unfortunately to date does not appear to be curable. When you see a patient initially, you need to think not only about what your frontline therapy is gonna be, but what your second line, your third line, and your fourth line therapy is gonna be, and plan it in a way that you're not burning any bridges. And in that regard, I think there's a couple of points that you can kind of take into Abecma. Taking the latter has been discussed here before, with Nick and Chip was saying, is the sequencing aspect, and there is burgeoning data. Not a lot yet, but there is burgeoning data both for Abecma and Carvykti, as Chip mentioned, that the outcome of patients with a BCMA CAR is better for patients who have never seen a BCMA-targeted therapy than for patients that have seen a BCMA-targeted therapy, be it a T-cell engager or an ADC. So again, that sequence of coming in first with your CAR and then following that when the patient recurs with a T-cell engager. So with these two principles, I think we're all gonna start to see in the studies, the KarMMa-3, the CARTITUDE-4, and now the two studies that are in upfront therapy, both with Abecma and Carvykti. I do think you are gonna see CAR earlier lines of therapy, potentially upfront, and then T-cell engagers are gonna be a critical part of the armamentarium, but they're likely gonna follow the CAR. In terms of upfront therapy, briefly, which gets to our KarMMa-9, we're incredibly excited about that, as Nick alluded to, because there it's possible that you may actually make the most impact in the treatment algorithms of patients. The approach that we with BMS are taking is, number one, transplant has been incredibly effective for myeloma. It's a mainstay in the treatment course of myeloma. Myeloma treating physicians are extremely comfortable with transplanting patients and understand all the nuances. It's being done mostly in many centers as an outpatient. But how do you improve upon that? Well, we know that at least 50%-60% of patients don't achieve a CR, and those patients have a worse outcome. And we believe that that's a significant unmet medical need that we can make a great impact to. As Nick alluded to, our KarMMa-2 Cohort C data, which was in a similar population, patients who've had less than a VGPR to transplant that got Abecma, did outstanding and much greater than historical controls with standard of care. All in all, I think you are gonna see this paradigm shifted over time, where the CAR is gonna be used earlier, and T-cell engagers are gonna be important part, as is other therapies, but likely are gonna come after. And as is multiple CARs. Right? That's kind of... Sure. Sure. Understood. I think the important aspect just is, the more therapies that physicians have in their toolbox, the better it is for patients. Got it. Okay. That's very helpful. You touched on KarMMa-9, so I think we should talk about that before time runs out. Just kind of educate us on where that program currently stands, what we can expect to learn over the next, call it a year or so. Well, I think, you know, and Chip, feel free to add in. Again, the premise of that is, as I mentioned, in patients who are treated upfront, they get their induction therapy, they get their transplant, they have less than an adequate response—they have an inadequate response to therapy, and then there'll be a randomized trial, with one arm being the use of Abecma in that setting. And for the rationale that I had just mentioned, and that study, we haven't yet disclosed the details of that, vis-à-vis sample size and what the- Okay Study is going to look like, but we're on track to begin enrollment later this year. And we think that it really could be an incredibly transformative approach. And we think it's also with a very high likelihood of success, again, based on the data that we've seen in KarMMa. These are not patients that have progressed. They're just suboptimal response, so you're still on the front line. Right. Because you don't want to wait for that progression. Right. So that's why we pound away at them right away again and get them hopefully into a CR. Got it. Right? And that's the objective, and we think that meets a better need than head-to-head. Right. I think that goes against the treatment paradigm, myeloma, unnecessarily. Just saying, there's a nice concept about that too, at least in my mind. Again, going back to basics of cancer therapy, you're treating these patients with an induction regimen, you're getting a response, and now you're coming in when they've had lower disease burden with two incredibly potent therapies that have different mechanism of action, transplant and then CAR. So there's something very attractive about the way that this is put together. Assuming success with KarMMa-9, where does that roughly 16,000 population, addressable population for Abecma jump to? It continues to grow. You know, this is, again, you kind of figure out where the truth lies, whether that's an additional, because this is a subset population, whether that's an additional 5-10,000 patients, whether you're in 20,000 or 25,000. Yep. You know, and then you can kind of start to say, well, it depends. You start to actually disturb the initial fork in the road about who's eligible for transplant, all of a sudden, that number starts to grow. So I think there's a. The only thing I've learned from listening to people's projections on market size is they're all considerably wrong. And I think you can see that even in the fifth line. And that is what I think Legend and J&J have pointed out, which is the numbers are swelling differently, right? And unfortunately, the patients aren't going away, right? Because it's not yet curative. And I think that's, that is a major difference between, what's happening in the CD19 space, where there is, thank God, a percent of patients that are being, knock on wood, cured. Right. Great. We'll get there, hopefully. About 2.5 minutes left. I'll just take a pause for any questions. If not, I will pivot to non-BCMA products. Okay, I see no questions. So let's go to SC-DARIC33. Just recap for us where the program stands following the hold, and what impact the restructuring has, if any, on forward movement with this program once you have alignment with the FDA on next steps. Yeah, and since we're a little short on time, I might just sort of jump in on those. Yeah. We're just working with SCRI, we're working with the FDA to make sure we understand how to restart that, trying to get it restarted as quickly as we can, and the restructuring doesn't really get in the way of that at all. Okay. The only thing we said is we are going to pause the next gen program till we have clarity with the FDA and we have clarity on sort of how those medicines are working. Before you start building on something, make sure that the base is solid, right? So I think that makes an awful lot of sense, and the restructuring just sort of codifies that. In the 369, it's a little bit different in the sense that I think we're continuing because we're excited about what we see, right? We've highlighted that, in a number of the press releases, but at the same time, want to make sure that people know that bar is high and we want to see sort of a pretty strong proof of concept in that phase I. So before we make at risk, sort of ramp up phase III investments. And so that's the other way to sort of, for lack of a better word, restructure the cost of that study. But both are playing out to their natural clinical endpoints, and that's the, sort of for lack of a better word, is the next steps in the two clinical programs. And that does push some of the readout in 369 into 2024. And people are saying, "When in 2024?" And we're saying, "We'll tell you when we have enough data on an enrollment that is a little slower than we would like for a bunch of reasons, but actually not interest." It has to do with the disease and the fact that sometimes those patients progress when you're trying to put them on- Right ... and so forth, and staggers and other types of things. This is stuff that our world, we're pretty used to, but it's frustrating. But at the same time, we were looking at the data that we're seeing, which does include CRs, et cetera, and we're at the dose that we believe is a real potential. And whether we have to go higher, we'll see. So we're running hard at 369, but it's gated. Mm-hmm. I think that's a different mindset that maybe will change, but it'll be based on data, and that will communicate in 2024. And the AML side of the equation, that's on... You know, we'll have to let people know once, when and if we figure out what's going on. Got it. My final question then for you is, on your cash runway guidance, you mentioned 2026+ post restructuring. Let's just assume 2026, just for the sake of the discussion and the math. What does that contemplate, especially given that some of the investments you mentioned are potentially gated, so how much flex is there for within that 2026 guidance? We've set that pretty conservatively, and that conservatism comes from a conservative view on Abecma. We're optimistic for all the reasons we've covered over the last 30 minutes about Abecma, but from a forecasting perspective, we've assumed conservatism in there. Look, there is a fan of outcomes if all of these phase 1 studies hit and we move all of them to pivotals, but that gets a lot more complex. But suffice to say, we're doing- We'll take that, though. We'll take... That's We'll take... That's a high-class problem, and in the meantime, we're doing what we can to control our destiny. Mm-hmm ... with the cost side of the equation, and we bought ourselves time to, to show a lot more, and we remain optimistic about that. So it has to do with the Abecma, right? Kind of, bracket, but also has to do with how we drive some more expense out of our system. And that's stuff that takes time, like real estate I was mentioning earlier. Sure. So we'll keep hammering away while we kind of keep the culture and the innovation focus, 2seventy strong. Great. All right. Well, with that, we should close out. Great. We're at time. Thank you so much for your time. Really appreciate it. Thank you, sir.