Lyell Immunopharma, Inc. — Call Transcript 2026

All right. Good afternoon, everyone. I'm Stephen Willey, one of the senior biotech analysts here at Stifel, and very glad to have with us in the next session, Lynn Seely, who is the President and CEO of Lyell. Lynn, thanks for joining us. Always appreciate it. Any opening statements you want to make or brief overview of the company you want to provide before we jump into Q&A? Sure. I'm happy to give an overview for those who may not be as familiar with Lyell. Maybe for the record, I should say I'll be making some forward-looking statements here, so consult our website. For those of you who don't know Lyell Immunopharma, we are a cell therapy company, and we're focused on next-generation cell therapies, both for patients with hematologic malignancies as well as for solid tumors. We have two lead programs in the clinic, both for large markets. One in large B-cell lymphoma, where we intend to displace the currently approved CD19 CARs, which have a $3 billion and growing marketplace. Then the second, a very novel CAR for metastatic colorectal cancer. Look forward to telling you about those. I should also just make note of the fact that Lyell is a little bit unique in that we have our own manufacturing life facility where we can launch from that facility and get well into launch with our own manufacturing. That puts control into our own destiny, which we really like. Yeah, that was great. Maybe before we get into any of the data development plans for the assets for ronde-cel specifically, maybe you can just first speak to what differentiates ronde-cel from the first generation of CD19 targeting CARs and other competitive offerings in the CD1920 space. I know you have some very unique attributes on the engineering front. You have a unique manufacturing process. How do those things, in your opinion, contribute to the clinical profile that you're seeing emerge? Our CAR product, this CD1920 construct, was very rationally designed by a brilliant engineer biologist at UCLA, her name's Dr. Yvonne Chen. This is a tandem CAR, it's a single CAR construct that binds either CD19 or CD20 with full potency. She meticulously did this work to ensure full potency at either, all in just one CAR construct. That's important because we are looking to get more complete responses and longer duration of response. We know that some malignant B cells that cause lymphoma have low CD19, may not respond well to CD19 therapy alone. With the CD1920, the dual targeting, we can drive more complete responses. One of the key mechanisms of escape from CD19 CARs is loss of antigen. These cancer cells are very smart, they can drop one antigen. It turns out it's much more difficult for them to drop two. That gives you longer duration of response. The third thing that is part of this product, which is quite novel, is that we are enriching our cell products for what we call CD62L positive cells. These are cells that are more naive fit T cells and have a tendency to persist longer and have more activity and can help us with a bit more softer safety profile. These features all come together to bring the product profile that we're looking for, which is more complete responses, more durable responses, and a nice safety profile. Okay. I know the data that we've seen for ronde-cel thus far, both in the second line and third-line plus settings of large cell B-cell lymphoma, certainly looks to be optically superior to what we've seen historically from the CD19 CARs in each respective setting. I know that comparison can be complicated by differences in eligibility criteria, baseline patient characteristics, disease characteristics across various studies. Can you just contextualize the safety and efficacy data that you are seeing with ronde-cel relative to the types of patients that you've specifically enrolled and treated within each setting? Sure. Maybe I'll just start with safety, because when we present safety data, we put our second and third-line patients together, so you can see the most patients. There, I think we're very proud of our safety profile. We have not seen any Grade 3 or higher cytokine release syndrome in the program. Our neurotoxicity or ICANS rate is single digit, less than 5%, so very competitive with respect to the currently approved CD19 CARs. You are exactly right. See, when you talk about whenever you're looking at lymphoma data set, you need to know who are you treating, because things make a difference in terms of the outcomes. Older patients don't do as well as younger patients. Patients with primary refractory disease don't do as well as patients, for example, with early or late relapse from their frontline therapy. Who you're studying really matters. We've put up data sets in both the second and the third line, which are really quite competitive. In the third or later line, we presented data at ASH where we were able to show a 93% overall response rate, a 76% complete response rate, and really importantly, a median progression-free survival of 18 months. How does that compare with the approved CD19 CARs? In their label, Yescarta and Breyanzi are relatively comparable. In terms of efficacy, they show about a 70% overall response rate and a 50% complete response rate. About 20 percentage points lower than we showed. More importantly, the median progression-free survival for the approved CD19 CARs is six to seven months. We have 18 months, it's not a subtle difference. This is really important because the primary endpoint of our trial in the third or later line is overall response rate, where we have 93% in the patients that we presented thus far. We are going to be having a significant data update in the back half of this year, where even more patients from that ongoing trial will be presented with even longer duration of response. That's the third line, which is, we think, a really important market for ronde-cel. In the second line, we also have put up a group of patients, a second-line cohort. Interestingly, these patients were almost completely primary refractory patients, so the sickest of the sick, those patients who don't even respond to frontline chemotherapy. There we were able to show an 83% overall response rate and a 61% complete response rate. That sounds a little bit lower than the third line, but it's because it's such a sick patient population. Again, when you compare to what data are available, you can find in Breyanzi literature for their single-arm study, a complete response rate in older, sicker patients like we enrolled of 42% in the primary refractory patient population. Again, much lower than what we're seeing. It's these data, particularly when you look at disease age and disease characteristics, that really tell us we're on the right track. When you look at the Breyanzi and Yescarta randomized controlled trials, they don't enroll any patients over the age of 75. We have no upper age limit, and we think this is really a great sign for our product profile. You're now in registration within this third line plus population, and you're doing that via the single-arm PiNACLE trial. Can you maybe just speak to the number of patients you're targeting for enrollment here? I know you've guided to a top-line data disclosure, I think in mid 2027, a BLA submission at the end of 2027. Will this update that you just referenced occurring in the back half of the year, will that include a meaningful amount of incremental patient data from the last cut, or will it just include a snapshot of durability from the last cut? We're going to be showing both. This is an ongoing trial, so we'll have more patients, we'll have longer duration of follow-up. You are right that our goal is to enroll about 120 patients. We need 100 treated patients to submit to the FDA. When we talk about the pivotal data set, what we're talking about is 100 treated patients approximately, who have been followed for at least six months after their first response. What that tells you is we'll be finishing up enrollment by the end of this year to stay on track for a mid-next year pivotal data disclosure. This is going to be a meaningful update, and I think we'll give investors a really great look at ronde-cel. As you know, the data have been quite consistent. We've had our recommended phase II dose as of the first data presentation, really, at Lugano. Last year, we presented at ASH. The data have really been quite consistent and promising. Okay. How would you characterize the current regulatory environment at FDA? We followed Arcellx. This was always a question we were getting from investors. Prasad is no longer at the helm of CBER. He was obviously a very vocal opponent of granting full approvals to CAR T therapy on the basis of single-arm data. I think penned an editorial in December that suggested that randomized OS data would be needed for full approvals in earlier lines of therapy. Have you just had any post-Prasad interactions with the agency on some of these topics? Do you think all of that was just bluster that's going to follow him out the door? Well, there has been a revolving door at the FDA for sure, I think I can say a few things. I think lymphoma is a place where there's a lot of precedent, where things like overall response rate correlate with overall survival quite well. Our FDA interactions to date have suggested that a full approval could be possible with this third or later line single-arm study. Worst case, an accelerated approval is just fine. We get on the market. What we have to have if we get accelerated approval is an ongoing randomized controlled trial, right? We have that. We have the gold standard of randomized controlled trials because we're currently treating patients in a head-to-head randomized controlled trial, ronde-cel versus investigator's choice of Breyanzi or Yescarta. Our development program fits squarely into whatever the FDA is going to require, whether it's accepting the third or later line for full approval, which they have done previously for Breyanzi and Yescarta. Remember, we have RMAT designation, which tells you that the FDA also agrees for us in both the second and third line that we're bringing a meaningful product, a product with meaningful data forward. We are getting the most attention there as their designations allow. I am very optimistic. In the worst case, we get accelerated approval, we're on the market, and then we bring in the head-to-head trial to confirm and convert that. Excellent. We're in a very good position, we believe, from a regulatory standpoint. Yeah, you initiated the head-to-head study you just referenced earlier this year. This is a pretty bold trial design, got a lot of press when it was rolled out, appropriately so. How do you think about the patient eligibility criteria in this study? How is it different in any way relative to TRANSFORM, the Breyanzi study, ZUMA-7, the Yescarta study, and how do you think those eligibility criteria may prove to be a competitive advantage for you, right? I know, for example, you mentioned that Breyanzi didn't study anyone over the age of 75. Can you just speak to that part of the study? Yeah. Look, we have a clear goal in mind. We want to displace the approved CD19 CARs. We have a development plan which is built to do that, and this head-to-head trial is designed very specifically to give doctors and patients the information that they're looking for. It's a superiority trial. It's a real-world trial, meaning that if you're eligible for CAR, you can be pretty much in this study. We don't have an upper age limit. We don't require testing for CD19 or 20 before you come in. We allow bridging therapy. We allow primary refractory disease, late relapses, early relapsers. It's a very real-world study. I would say in comparison, when the randomized controlled trials were done with Breyanzi and Yescarta, they didn't take patients over the age of 75. Yescarta didn't allow bridging therapy. Even today, you may be aware that Kite Gilead is going to run a head-to-head. Yeah have a different CD19/20 in development, and they're about a year behind us because it takes about a year to get these sites activated. We've been working on our program for well over a year. They're not allowing bridging therapy, and they're only randomizing patients to Yescarta. We're allowing randomization for the investigator to pick either Yescarta or Breyanzi. A little bit more real world, and we think that's going to be very much to our advantage. Yeah. Given how the market share appears to have split out between Breyanzi and Yescarta, that may represent a competitive disadvantage for them in terms of enrollment accrual. You talked about the Kite product, right? I know in your opening statement you referenced a tandem binder that was engineered into ronde-cel. Kite uses this bicistronic binder. How do you think just that engineering difference alone gives you a leg up as you think about comparing and contrasting the two products in this setting? Yeah, I think the data are going to speak for themselves as time goes by. I have to speak in theoreticals. I think what typically is thought of is that a tandem CAR means there's one CAR expressed, so that's advantageous to the cell. If you have two CARs expressed, it's more metabolically difficult for the CAR to express two. In this case, in the case of Kite, they're expressing Yescarta for the CD19 component and then a CD20, a separate CAR. That is some metabolic stress. It's a little bit more difficult in manufacturing, isn't it, to make sure you get consistent expression of both over time? There's some school of thought that having these two different CARs, one with a CD28 costimulatory domain, may lead to more T-cell exhaustion, which would not be good for durability. These are theoretics. We're going to have to see how the data play out. Right now, we are very pleased with the performance of our tandem CAR, both in terms of the complete response rates we're seeing and, very importantly, the durability and the safety profile. Okay. J&J recently announced- that it was discontinuing its CD19, CD20 dual CAR T program. Do you think that this reflects any read-through in terms of their interpretation or perspective of the competitive landscape or commercial opportunity, or do you think this was just probably an isolated asset-specific decision that the company made? Well, one can never know what goes on inside of Johnson & Johnson. I think obviously they said it was a business decision. I have to believe it did have to do with the competitive landscape, but maybe not in the way people think. We know that J&J licensed their product from China from a company known as AbelZeta. We know that they were having some trouble with dose finding because the dose used in China to present some very nice data was about 150 million cells. They'd already dropped back to about 75 million cells, which implies something was happening. Interestingly, they didn't show up at ASH with any new clinical data, which was sort of surprising, the big hematologic cancer meetings at the end of the year. They pulled out altogether. I think one of the things that we know we did was we went out very early with this head-to-head study. We got all the major sites agreeing to participate in our study. We put up our steering committee. Over time, we knew that J&J was going to these same sites and saying, "Oh, we want to run a study." They were told, "No. Well, we've already committed to Lyell, and we're working with Lyell in the study." We turned them down. It could be Johnson & Johnson doesn't like to be second, right? Or third. They like to be the leader, particularly in a marketplace like this. It's possible that they just got behind and decided that it wasn't worth it for them to be the third head-to-head trial ongoing. I think we took a very aggressive strategy, and I think it paid off. For whatever reason, doesn't matter, this is great news for Lyell because it's one less significant competitor in the marketplace, and we think we're clearly in the lead at this point, and not by a small margin. The onus is on us to continue this aggressive execution and stay on track to have this major data update at the second half of this year and then get that BLA submitted next year. Okay. Any thoughts on what Allogene's trying to do with their ALPHA3 trial, where they're looking at cema-cel as consolidation therapy and in patients who are MRD positive, absent clinical progression, post frontline therapy, do you think that success for them in that study somehow impacts the market opportunity in the second line setting? Well, I think any success in cell therapy is good. I'm always happy when cell therapy companies do well, like Arcellx being acquired because all boats float. I think in terms of threatening ronde-cel, no. I think this is an allogeneic product. They showed some futility data that in 24 patients, 12 in each arm, showed that they were able to achieve MRD negative status. They've got a ways to go. We didn't get any durability data. It wasn't the primary endpoint of the study, they've got a ways to go, for us, it's a small patient population. It's not going to take away the major percent of the population because when you look at, even if they're 20% or 25% of patients are MRD positive after frontline therapy, half of them get testing and get cema-cel. It's not a major drawback for us. I'm happy for them. I wish them the best of luck, but I don't think this is a threat to ronde-cel. Okay. One more competitor question then. Okay. I'll stop. Legend just announced that they're going to be presenting some preliminary data for a in vivo 19/20 product at a medical meeting sometime later this year. I'm sure you're going to get this question asked a lot, if not already, how do you just think about in vivo CAR T as an existential threat to autologous and even allogeneic cell therapy within the setting of oncology specifically? In vivo is very exciting. It's a new technology. Autologous CAR T-cell therapy has been around for a decade plus. We understand it a lot. We've worked hard to get this next generation CAR T-cell therapy. We are very excited about in vivo and interested in it as well. If I were going to say, does this threaten ronde-cel, I would say no, I think it's complementary because Legend's going to put out their data. What are they going to have to do to threaten ronde-cel? Three things. They're going to have to put up complete response rates or overall response rates that are 90%, complete response rates that are 76%, which is what we've presented, and more importantly, median progression-free survival of 18 months. They just dosed their first patient in the summer. They're not going to be able to have that, plus safety. That's a lot of variables that have to be hit first time up at bat with a very new technology. Can in vivo get there? Maybe over time, but it's not going to be as soon as maybe people currently think it is. This is a study done in China. It's going to have to be repeated, even if it is the be-all end-all. I think where I sort of see in vivo being very important, autologous CAR is the gold standard, and our CD19/CD20, I think is putting up data best in class. We believe we're going to be able to improve access because the value proposition for patients and for providers is improving. In vivo CAR can extend that access. That's a great thing for patients and the field at large. Do I think in vivo first time up at bat is going to replace and threaten autologous CAR? Maybe, but I'd be surprised. Okay. Maybe the last few minutes we can switch gears to LYL273. This is the GC-C targeting CAR that you licensed last year. Very unique mechanism of action. Can you explain the rationale for adding a separate CD19 CAR along with the CAR that's targeting GC-C that's expressed on tumor cells? What does that buy you from a biological perspective? CAR T-cell therapy in solid tumors is hard. A lot of CAR T-cell therapies have failed. They may have had a good target, but that was not sufficient. It's necessary, but not sufficient. Guanylyl cyclase-C or GC-C is a great target for metastatic colorectal cancer because it's upregulated in more than 95% of them. We know a target alone is not sufficient, and the inventor of this CAR realized that there were two main barriers that had to be overcome. One is we need more cell expansion, and two is we need some way to make the hostile tumor microenvironment warmer, more friendly to these CAR T-cells so they don't just rapidly exhaust and die. The concept is there's GC-C CAR expressed, this is a dual targeting product, and separate, this is a CD19 CAR expressed. Here what you have is a CD19 CAR is engineered to release cytokines or supportive hormones, you can think of it as. CD19, you're like, "Whoa, that's a B-cell target." Yeah, intentionally. There is 1 day of lymphodepletion, so when this product is infused, B-cells remain. The cells hit the B-cells, they activate, they release cytokines. This jumpstarts cell expansion, and in particular, we get nice expansion of these, what we call doublet cells, which have both CD19 and GC-C, which can get into the tumor with secretion of cytokines and warm up that tumor microenvironment. Then the largest number of cells are GC-C alone. They get in and kill the tumor. We've been seeing response rates across two dose levels in the 50% range. It's an active CAR. This novel mechanism, we think, is really something that's not been studied before. It's very unique. It's very next generation. I think that's why we're seeing the activity that we are. Okay. I know you've guided to having a couple of incremental clinical updates from this program later this year. What should we be expecting to see in conjunction with each of those disclosures? We're in the first half coming soon, we're going to have an update on the program. A lot of that is going to focus on safety because one of the side effects of this product is some diarrhea, and there was one patient who did get a pretty significant colitis that required some significant immunosuppressive therapy. The patient actually died from an infection. The colitis was controlled but got a subsequent infection. When he died, he had an autopsy. There was no evidence of disease. Again, this is an active CAR, but we need to show that we can manage the diarrhea. After this case, a significant prophylactic regimen was put in place with a safety management plan. We're going to be updating on the next round of patients that were treated with that safety management plan, and to give investors an idea if we can control and manage appropriately the diarrhea. In the back half, we'll have a more fulsome update at a medical conference, where we'll be giving outcomes data as well. Okay. You've suggested that peak capacity at your facility for ronde-cel, I believe, is around 1,200 doses a year. How do you accommodate 273 into your manufacturing plans? Are you tech transferring that in? What are your options to scale capacity for each of these products? That's a great question. We do have our own manufacturing facility. It's state of the art. It's all paperless. We are running right now for ronde-cel, our commercial manufacturing process, and we can manufacture more than 1,200 doses per year, which can get us well into launch. We are transferring in this GC-C CAR program. It's very automated, so it's sort of made on the CliniMACS Prodigy, and it's quite easy and standard to run. For the time being, we can do both, and again, we can launch ronde-cel without difficulty. Over time, we'll need more capacity, more space, but again, that's a great problem for us to have, and it's not a near-term capital requirement. We can get far into launch before we need to go there. Okay. I think we can do both within our facility. Okay. Just lastly, speaking of capital requirement, what is the current balance sheet, and what does that allow you to execute on here as you go forward? The great news for us is we have, as we've just spoken about, some data-rich catalysts coming up here in the next period of time. We have, as of our Q1 filing, we had $261 million in cash, and that gets us through Q3 of next year and through these catalysts, including the pivotal data. All right. Well, we're out of time, Lynn. I really appreciate it. That was great. Thanks everyone for listening. All right. Thank you.

Speaker 2: All right. Good afternoon, everyone. I'm Stephen Willey, one of the senior biotech analysts here at Stifel, and very glad to have with us in the next session, Lynn Seely, who is the President and CEO of Lyell. Lynn, thanks for joining us. Always appreciate it. Any opening statements you want to make or brief overview of the company you want to provide before we jump into Q&A? All right. all right Good afternoon, everyone. good afternoon everyone I'm Stephen Willey, one of the senior biotech analysts here at Stifel, and very glad to have with us in the next session, Lynn Seely, who is the President and CEO of Lyell. i'm stephen willey one of the senior biotech analysts here at stifel and very glad to have with us in the next session lynn seely who is the president and ceo of lyell Lynn, thanks for joining us. lynn thanks for joining us Always appreciate it. always appreciate it Any opening statements you want to make or brief overview of the company you want to provide before we jump into Q&A? any opening statements you want to make or brief overview of the company you want to provide before we jump into q&a

Speaker 1: Sure. I'm happy to give an overview for those who may not be as familiar with Lyell. Maybe for the record, I should say I'll be making some forward-looking statements here, so consult our website. For those of you who don't know Lyell Immunopharma, we are a cell therapy company, and we're focused on next-generation cell therapies, both for patients with hematologic malignancies as well as for solid tumors. We have two lead programs in the clinic, both for large markets. One in large B-cell lymphoma, where we intend to displace the currently approved CD19 CARs, which have a $3 billion and growing marketplace. Then the second, a very novel CAR for metastatic colorectal cancer. Look forward to telling you about those. Sure. sure I'm happy to give an overview for those who may not be as familiar with Lyell. i'm happy to give an overview for those who may not be as familiar with lyell Maybe for the record, I should say I'll be making some forward-looking statements here, so consult our website. maybe for the record i should say i'll be making some forward-looking statements here so consult our website For those of you who don't know Lyell Immunopharma, we are a cell therapy company, and we're focused on next-generation cell therapies, both for patients with hematologic malignancies as well as for solid tumors. for those of you who don't know lyell immunopharma we are a cell therapy company and we're focused on next-generation cell therapies both for patients with hematologic malignancies as well as for solid tumors We have two lead programs in the clinic, both for large markets. we have two lead programs in the clinic both for large markets One in large B-cell lymphoma, where we intend to displace the currently approved CD19 CARs, which have a $3 billion and growing marketplace. one in large b-cell lymphoma where we intend to displace the currently approved cd19 cars which have a $3 billion and growing marketplace Then the second, a very novel CAR for metastatic colorectal cancer. then the second a very novel car for metastatic colorectal cancer Look forward to telling you about those. look forward to telling you about those I should also just make note of the fact that Lyell is a little bit unique in that we have our own manufacturing life facility where we can launch from that facility and get well into launch with our own manufacturing. That puts control into our own destiny, which we really like. I should also just make note of the fact that Lyell is a little bit unique in that we have our own manufacturing life facility where we can launch from that facility and get well into launch with our own manufacturing. i should also just make note of the fact that lyell is a little bit unique in that we have our own manufacturing life facility where we can launch from that facility and get well into launch with our own manufacturing That puts control into our own destiny, which we really like. that puts control into our own destiny which we really like

Speaker 2: Yeah, that was great. Maybe before we get into any of the data development plans for the assets for ronde-cel specifically, maybe you can just first speak to what differentiates ronde-cel from the first generation of CD19 targeting CARs and other competitive offerings in the CD1920 space. I know you have some very unique attributes on the engineering front. You have a unique manufacturing process. How do those things, in your opinion, contribute to the clinical profile that you're seeing emerge? Yeah, that was great. yeah that was great Maybe before we get into any of the data development plans for the assets for ronde-cel specifically, maybe you can just first speak to what differentiates ronde-cel from the first generation of CD19 targeting CARs and other competitive offerings in the CD1920 space. maybe before we get into any of the data development plans for the assets for ronde-cel specifically maybe you can just first speak to what differentiates ronde-cel from the first generation of cd19 targeting cars and other competitive offerings in the cd1920 space I know you have some very unique attributes on the engineering front. i know you have some very unique attributes on the engineering front You have a unique manufacturing process. you have a unique manufacturing process How do those things, in your opinion, contribute to the clinical profile that you're seeing emerge? how do those things in your opinion contribute to the clinical profile that you're seeing emerge

Speaker 1: Our CAR product, this CD1920 construct, was very rationally designed by a brilliant engineer biologist at UCLA, her name's Dr. Yvonne Chen. This is a tandem CAR, it's a single CAR construct that binds either CD19 or CD20 with full potency. She meticulously did this work to ensure full potency at either, all in just one CAR construct. That's important because we are looking to get more complete responses and longer duration of response. We know that some malignant B cells that cause lymphoma have low CD19, may not respond well to CD19 therapy alone. With the CD1920, the dual targeting, we can drive more complete responses. One of the key mechanisms of escape from CD19 CARs is loss of antigen. These cancer cells are very smart, they can drop one antigen. Our CAR product, this CD1920 construct, was very rationally designed by a brilliant engineer biologist at UCLA, her name's Dr. Yvonne Chen. our car product this cd1920 construct was very rationally designed by a brilliant engineer biologist at ucla her name's dr yvonne chen This is a tandem CAR, it's a single CAR construct that binds either CD19 or CD20 with full potency. this is a tandem car it's a single car construct that binds either cd19 or cd20 with full potency She meticulously did this work to ensure full potency at either, all in just one CAR construct. she meticulously did this work to ensure full potency at either all in just one car construct That's important because we are looking to get more complete responses and longer duration of response. that's important because we are looking to get more complete responses and longer duration of response We know that some malignant B cells that cause lymphoma have low CD19, may not respond well to CD19 therapy alone. we know that some malignant b cells that cause lymphoma have low cd19 may not respond well to cd19 therapy alone With the CD1920, the dual targeting, we can drive more complete responses. with the cd1920 the dual targeting we can drive more complete responses One of the key mechanisms of escape from CD19 CARs is loss of antigen. one of the key mechanisms of escape from cd19 cars is loss of antigen These cancer cells are very smart, they can drop one antigen. these cancer cells are very smart they can drop one antigen It turns out it's much more difficult for them to drop two. That gives you longer duration of response. The third thing that is part of this product, which is quite novel, is that we are enriching our cell products for what we call CD62L positive cells. These are cells that are more naive fit T cells and have a tendency to persist longer and have more activity and can help us with a bit more softer safety profile. These features all come together to bring the product profile that we're looking for, which is more complete responses, more durable responses, and a nice safety profile. It turns out it's much more difficult for them to drop two. it turns out it's much more difficult for them to drop two That gives you longer duration of response. that gives you longer duration of response The third thing that is part of this product, which is quite novel, is that we are enriching our cell products for what we call CD62L positive cells. the third thing that is part of this product which is quite novel is that we are enriching our cell products for what we call cd62l positive cells These are cells that are more naive fit T cells and have a tendency to persist longer and have more activity and can help us with a bit more softer safety profile. these are cells that are more naive fit t cells and have a tendency to persist longer and have more activity and can help us with a bit more softer safety profile These features all come together to bring the product profile that we're looking for, which is more complete responses, more durable responses, and a nice safety profile. these features all come together to bring the product profile that we're looking for which is more complete responses more durable responses and a nice safety profile

Speaker 2: Okay. I know the data that we've seen for ronde-cel thus far, both in the second line and third-line plus settings of large cell B-cell lymphoma, certainly looks to be optically superior to what we've seen historically from the CD19 CARs in each respective setting. I know that comparison can be complicated by differences in eligibility criteria, baseline patient characteristics, disease characteristics across various studies. Can you just contextualize the safety and efficacy data that you are seeing with ronde-cel relative to the types of patients that you've specifically enrolled and treated within each setting? Okay. okay I know the data that we've seen for ronde-cel thus far, both in the second line and third-line plus settings of large cell B-cell lymphoma, certainly looks to be optically superior to what we've seen historically from the CD19 CARs in each respective setting. i know the data that we've seen for ronde-cel thus far both in the second line and third-line plus settings of large cell b-cell lymphoma certainly looks to be optically superior to what we've seen historically from the cd19 cars in each respective setting I know that comparison can be complicated by differences in eligibility criteria, baseline patient characteristics, disease characteristics across various studies. i know that comparison can be complicated by differences in eligibility criteria baseline patient characteristics disease characteristics across various studies Can you just contextualize the safety and efficacy data that you are seeing with ronde-cel relative to the types of patients that you've specifically enrolled and treated within each setting? can you just contextualize the safety and efficacy data that you are seeing with ronde-cel relative to the types of patients that you've specifically enrolled and treated within each setting

Speaker 1: Sure. Maybe I'll just start with safety, because when we present safety data, we put our second and third-line patients together, so you can see the most patients. There, I think we're very proud of our safety profile. We have not seen any Grade 3 or higher cytokine release syndrome in the program. Our neurotoxicity or ICANS rate is single digit, less than 5%, so very competitive with respect to the currently approved CD19 CARs. You are exactly right. See, when you talk about whenever you're looking at lymphoma data set, you need to know who are you treating, because things make a difference in terms of the outcomes. Older patients don't do as well as younger patients. Patients with primary refractory disease don't do as well as patients, for example, with early or late relapse from their frontline therapy. Who you're studying really matters. Sure. sure Maybe I'll just start with safety, because when we present safety data, we put our second and third-line patients together, so you can see the most patients. maybe i'll just start with safety because when we present safety data we put our second and third-line patients together so you can see the most patients There, I think we're very proud of our safety profile. there i think we're very proud of our safety profile We have not seen any Grade 3 or higher cytokine release syndrome in the program. we have not seen any grade 3 or higher cytokine release syndrome in the program Our neurotoxicity or ICANS rate is single digit, less than 5%, so very competitive with respect to the currently approved CD19 CARs. our neurotoxicity or icans rate is single digit less than 5% so very competitive with respect to the currently approved cd19 cars You are exactly right. you are exactly right See, when you talk about whenever you're looking at lymphoma data set, you need to know who are you treating, because things make a difference in terms of the outcomes. see when you talk about whenever you're looking at lymphoma data set you need to know who are you treating because things make a difference in terms of the outcomes Older patients don't do as well as younger patients. older patients don't do as well as younger patients Patients with primary refractory disease don't do as well as patients, for example, with early or late relapse from their frontline therapy. patients with primary refractory disease don't do as well as patients for example with early or late relapse from their frontline therapy Who you're studying really matters. who you're studying really matters We've put up data sets in both the second and the third line, which are really quite competitive. In the third or later line, we presented data at ASH where we were able to show a 93% overall response rate, a 76% complete response rate, and really importantly, a median progression-free survival of 18 months. How does that compare with the approved CD19 CARs? In their label, Yescarta and Breyanzi are relatively comparable. In terms of efficacy, they show about a 70% overall response rate and a 50% complete response rate. About 20 percentage points lower than we showed. More importantly, the median progression-free survival for the approved CD19 CARs is six to seven months. We have 18 months, it's not a subtle difference. We've put up data sets in both the second and the third line, which are really quite competitive. we've put up data sets in both the second and the third line which are really quite competitive In the third or later line, we presented data at ASH where we were able to show a 93% overall response rate, a 76% complete response rate, and really importantly, a median progression-free survival of 18 months. in the third or later line we presented data at ash where we were able to show a 93% overall response rate a 76% complete response rate and really importantly a median progression-free survival of 18 months How does that compare with the approved CD19 CARs? how does that compare with the approved cd19 cars In their label, Yescarta and Breyanzi are relatively comparable. in their label yescarta and breyanzi are relatively comparable In terms of efficacy, they show about a 70% overall response rate and a 50% complete response rate. in terms of efficacy they show about a 70% overall response rate and a 50% complete response rate About 20 percentage points lower than we showed. about 20 percentage points lower than we showed More importantly, the median progression-free survival for the approved CD19 CARs is six to seven months. more importantly the median progression-free survival for the approved cd19 cars is six to seven months We have 18 months, it's not a subtle difference. we have 18 months it's not a subtle difference This is really important because the primary endpoint of our trial in the third or later line is overall response rate, where we have 93% in the patients that we presented thus far. We are going to be having a significant data update in the back half of this year, where even more patients from that ongoing trial will be presented with even longer duration of response. That's the third line, which is, we think, a really important market for ronde-cel. In the second line, we also have put up a group of patients, a second-line cohort. Interestingly, these patients were almost completely primary refractory patients, so the sickest of the sick, those patients who don't even respond to frontline chemotherapy. There we were able to show an 83% overall response rate and a 61% complete response rate. This is really important because the primary endpoint of our trial in the third or later line is overall response rate, where we have 93% in the patients that we presented thus far. this is really important because the primary endpoint of our trial in the third or later line is overall response rate where we have 93% in the patients that we presented thus far We are going to be having a significant data update in the back half of this year, where even more patients from that ongoing trial will be presented with even longer duration of response. we are going to be having a significant data update in the back half of this year where even more patients from that ongoing trial will be presented with even longer duration of response That's the third line, which is, we think, a really important market for ronde-cel. that's the third line which is we think a really important market for ronde-cel In the second line, we also have put up a group of patients, a second-line cohort. in the second line we also have put up a group of patients a second-line cohort Interestingly, these patients were almost completely primary refractory patients, so the sickest of the sick, those patients who don't even respond to frontline chemotherapy. interestingly these patients were almost completely primary refractory patients so the sickest of the sick those patients who don't even respond to frontline chemotherapy There we were able to show an 83% overall response rate and a 61% complete response rate. there we were able to show an 83% overall response rate and a 61% complete response rate That sounds a little bit lower than the third line, but it's because it's such a sick patient population. Again, when you compare to what data are available, you can find in Breyanzi literature for their single-arm study, a complete response rate in older, sicker patients like we enrolled of 42% in the primary refractory patient population. Again, much lower than what we're seeing. It's these data, particularly when you look at disease age and disease characteristics, that really tell us we're on the right track. When you look at the Breyanzi and Yescarta randomized controlled trials, they don't enroll any patients over the age of 75. We have no upper age limit, and we think this is really a great sign for our product profile. That sounds a little bit lower than the third line, but it's because it's such a sick patient population. that sounds a little bit lower than the third line but it's because it's such a sick patient population Again, when you compare to what data are available, you can find in Breyanzi literature for their single-arm study, a complete response rate in older, sicker patients like we enrolled of 42% in the primary refractory patient population. again when you compare to what data are available you can find in breyanzi literature for their single-arm study a complete response rate in older sicker patients like we enrolled of 42% in the primary refractory patient population Again, much lower than what we're seeing. again much lower than what we're seeing It's these data, particularly when you look at disease age and disease characteristics, that really tell us we're on the right track. it's these data particularly when you look at disease age and disease characteristics that really tell us we're on the right track When you look at the Breyanzi and Yescarta randomized controlled trials, they don't enroll any patients over the age of 75. when you look at the breyanzi and yescarta randomized controlled trials they don't enroll any patients over the age of 75 We have no upper age limit, and we think this is really a great sign for our product profile. we have no upper age limit and we think this is really a great sign for our product profile

Speaker 2: You're now in registration within this third line plus population, and you're doing that via the single-arm PiNACLE trial. Can you maybe just speak to the number of patients you're targeting for enrollment here? I know you've guided to a top-line data disclosure, I think in mid 2027, a BLA submission at the end of 2027. Will this update that you just referenced occurring in the back half of the year, will that include a meaningful amount of incremental patient data from the last cut, or will it just include a snapshot of durability from the last cut? You're now in registration within this third line plus population, and you're doing that via the single-arm PiNACLE trial. you're now in registration within this third line plus population and you're doing that via the single-arm pinacle trial Can you maybe just speak to the number of patients you're targeting for enrollment here? can you maybe just speak to the number of patients you're targeting for enrollment here I know you've guided to a top-line data disclosure, I think in mid 2027, a BLA submission at the end of 2027. i know you've guided to a top-line data disclosure i think in mid 2027 a bla submission at the end of 2027 Will this update that you just referenced occurring in the back half of the year, will that include a meaningful amount of incremental patient data from the last cut, or will it just include a snapshot of durability from the last cut? will this update that you just referenced occurring in the back half of the year will that include a meaningful amount of incremental patient data from the last cut or will it just include a snapshot of durability from the last cut

Speaker 1: We're going to be showing both. This is an ongoing trial, so we'll have more patients, we'll have longer duration of follow-up. You are right that our goal is to enroll about 120 patients. We need 100 treated patients to submit to the FDA. When we talk about the pivotal data set, what we're talking about is 100 treated patients approximately, who have been followed for at least six months after their first response. What that tells you is we'll be finishing up enrollment by the end of this year to stay on track for a mid-next year pivotal data disclosure. This is going to be a meaningful update, and I think we'll give investors a really great look at ronde-cel. As you know, the data have been quite consistent. We're going to be showing both. we're going to be showing both This is an ongoing trial, so we'll have more patients, we'll have longer duration of follow-up. this is an ongoing trial so we'll have more patients we'll have longer duration of follow-up You are right that our goal is to enroll about 120 patients. you are right that our goal is to enroll about 120 patients We need 100 treated patients to submit to the FDA. we need 100 treated patients to submit to the fda When we talk about the pivotal data set, what we're talking about is 100 treated patients approximately, who have been followed for at least six months after their first response. when we talk about the pivotal data set what we're talking about is 100 treated patients approximately who have been followed for at least six months after their first response What that tells you is we'll be finishing up enrollment by the end of this year to stay on track for a mid-next year pivotal data disclosure. what that tells you is we'll be finishing up enrollment by the end of this year to stay on track for a mid-next year pivotal data disclosure This is going to be a meaningful update, and I think we'll give investors a really great look at ronde-cel. this is going to be a meaningful update and i think we'll give investors a really great look at ronde-cel As you know, the data have been quite consistent. as you know the data have been quite consistent We've had our recommended phase II dose as of the first data presentation, really, at Lugano. Last year, we presented at ASH. The data have really been quite consistent and promising. We've had our recommended phase II dose as of the first data presentation, really, at Lugano. we've had our recommended phase ii dose as of the first data presentation really at lugano Last year, we presented at ASH. last year we presented at ash The data have really been quite consistent and promising. the data have really been quite consistent and promising

Speaker 2: Okay. How would you characterize the current regulatory environment at FDA? We followed Arcellx. This was always a question we were getting from investors. Prasad is no longer at the helm of CBER. He was obviously a very vocal opponent of granting full approvals to CAR T therapy on the basis of single-arm data. I think penned an editorial in December that suggested that randomized OS data would be needed for full approvals in earlier lines of therapy. Have you just had any post-Prasad interactions with the agency on some of these topics? Do you think all of that was just bluster that's going to follow him out the door? Okay. okay How would you characterize the current regulatory environment at FDA? how would you characterize the current regulatory environment at fda We followed Arcellx. we followed arcellx This was always a question we were getting from investors. this was always a question we were getting from investors Prasad is no longer at the helm of CBER. prasad is no longer at the helm of cber He was obviously a very vocal opponent of granting full approvals to CAR T therapy on the basis of single-arm data. he was obviously a very vocal opponent of granting full approvals to car t therapy on the basis of single-arm data I think penned an editorial in December that suggested that randomized OS data would be needed for full approvals in earlier lines of therapy. i think penned an editorial in december that suggested that randomized os data would be needed for full approvals in earlier lines of therapy Have you just had any post-Prasad interactions with the agency on some of these topics? have you just had any post-prasad interactions with the agency on some of these topics Do you think all of that was just bluster that's going to follow him out the door? do you think all of that was just bluster that's going to follow him out the door

Speaker 1: Well, there has been a revolving door at the FDA for sure, I think I can say a few things. I think lymphoma is a place where there's a lot of precedent, where things like overall response rate correlate with overall survival quite well. Our FDA interactions to date have suggested that a full approval could be possible with this third or later line single-arm study. Worst case, an accelerated approval is just fine. We get on the market. What we have to have if we get accelerated approval is an ongoing randomized controlled trial, right? Well, there has been a revolving door at the FDA for sure, I think I can say a few things. well there has been a revolving door at the fda for sure i think i can say a few things I think lymphoma is a place where there's a lot of precedent, where things like overall response rate correlate with overall survival quite well. i think lymphoma is a place where there's a lot of precedent where things like overall response rate correlate with overall survival quite well Our FDA interactions to date have suggested that a full approval could be possible with this third or later line single-arm study. our fda interactions to date have suggested that a full approval could be possible with this third or later line single-arm study Worst case, an accelerated approval is just fine. worst case an accelerated approval is just fine We get on the market. we get on the market What we have to have if we get accelerated approval is an ongoing randomized controlled trial, right? what we have to have if we get accelerated approval is an ongoing randomized controlled trial right We have that. We have the gold standard of randomized controlled trials because we're currently treating patients in a head-to-head randomized controlled trial, ronde-cel versus investigator's choice of Breyanzi or Yescarta. Our development program fits squarely into whatever the FDA is going to require, whether it's accepting the third or later line for full approval, which they have done previously for Breyanzi and Yescarta. Remember, we have RMAT designation, which tells you that the FDA also agrees for us in both the second and third line that we're bringing a meaningful product, a product with meaningful data forward. We are getting the most attention there as their designations allow. I am very optimistic. In the worst case, we get accelerated approval, we're on the market, and then we bring in the head-to-head trial to confirm and convert that. We have that. we have that We have the gold standard of randomized controlled trials because we're currently treating patients in a head-to-head randomized controlled trial, ronde-cel versus investigator's choice of Breyanzi or Yescarta. we have the gold standard of randomized controlled trials because we're currently treating patients in a head-to-head randomized controlled trial ronde-cel versus investigator's choice of breyanzi or yescarta Our development program fits squarely into whatever the FDA is going to require, whether it's accepting the third or later line for full approval, which they have done previously for Breyanzi and Yescarta. our development program fits squarely into whatever the fda is going to require whether it's accepting the third or later line for full approval which they have done previously for breyanzi and yescarta Remember, we have RMAT designation, which tells you that the FDA also agrees for us in both the second and third line that we're bringing a meaningful product, a product with meaningful data forward. remember we have rmat designation which tells you that the fda also agrees for us in both the second and third line that we're bringing a meaningful product a product with meaningful data forward We are getting the most attention there as their designations allow. we are getting the most attention there as their designations allow I am very optimistic. i am very optimistic In the worst case, we get accelerated approval, we're on the market, and then we bring in the head-to-head trial to confirm and convert that. in the worst case we get accelerated approval we're on the market and then we bring in the head-to-head trial to confirm and convert that

Speaker 2: Excellent. Excellent. excellent

Speaker 1: We're in a very good position, we believe, from a regulatory standpoint. We're in a very good position, we believe, from a regulatory standpoint. we're in a very good position we believe from a regulatory standpoint

Speaker 2: Yeah, you initiated the head-to-head study you just referenced earlier this year. This is a pretty bold trial design, got a lot of press when it was rolled out, appropriately so. How do you think about the patient eligibility criteria in this study? How is it different in any way relative to TRANSFORM, the Breyanzi study, ZUMA-7, the Yescarta study, and how do you think those eligibility criteria may prove to be a competitive advantage for you, right? I know, for example, you mentioned that Breyanzi didn't study anyone over the age of 75. Can you just speak to that part of the study? Yeah, you initiated the head-to-head study you just referenced earlier this year. yeah you initiated the head-to-head study you just referenced earlier this year This is a pretty bold trial design, got a lot of press when it was rolled out, appropriately so. How do you think about the patient eligibility criteria in this study? this is a pretty bold trial design got a lot of press when it was rolled out appropriately so. how do you think about the patient eligibility criteria in this study How is it different in any way relative to TRANSFORM, the Breyanzi study, ZUMA-7, the Yescarta study, and how do you think those eligibility criteria may prove to be a competitive advantage for you, right? how is it different in any way relative to transform the breyanzi study zuma-7 the yescarta study and how do you think those eligibility criteria may prove to be a competitive advantage for you right I know, for example, you mentioned that Breyanzi didn't study anyone over the age of 75. i know for example you mentioned that breyanzi didn't study anyone over the age of 75 Can you just speak to that part of the study? can you just speak to that part of the study

Speaker 1: Yeah. Look, we have a clear goal in mind. We want to displace the approved CD19 CARs. We have a development plan which is built to do that, and this head-to-head trial is designed very specifically to give doctors and patients the information that they're looking for. It's a superiority trial. It's a real-world trial, meaning that if you're eligible for CAR, you can be pretty much in this study. We don't have an upper age limit. We don't require testing for CD19 or 20 before you come in. We allow bridging therapy. We allow primary refractory disease, late relapses, early relapsers. It's a very real-world study. I would say in comparison, when the randomized controlled trials were done with Breyanzi and Yescarta, they didn't take patients over the age of 75. Yescarta didn't allow bridging therapy. Yeah. yeah Look, we have a clear goal in mind. look we have a clear goal in mind We want to displace the approved CD19 CARs. we want to displace the approved cd19 cars We have a development plan which is built to do that, and this head-to-head trial is designed very specifically to give doctors and patients the information that they're looking for. we have a development plan which is built to do that and this head-to-head trial is designed very specifically to give doctors and patients the information that they're looking for It's a superiority trial. it's a superiority trial It's a real-world trial, meaning that if you're eligible for CAR, you can be pretty much in this study. it's a real-world trial meaning that if you're eligible for car you can be pretty much in this study We don't have an upper age limit. we don't have an upper age limit We don't require testing for CD19 or 20 before you come in. we don't require testing for cd19 or 20 before you come in We allow bridging therapy. we allow bridging therapy We allow primary refractory disease, late relapses, early relapsers. we allow primary refractory disease late relapses early relapsers It's a very real-world study. it's a very real-world study I would say in comparison, when the randomized controlled trials were done with Breyanzi and Yescarta, they didn't take patients over the age of 75. i would say in comparison when the randomized controlled trials were done with breyanzi and yescarta they didn't take patients over the age of 75 Yescarta didn't allow bridging therapy. yescarta didn't allow bridging therapy Even today, you may be aware that Kite Gilead is going to run a head-to-head. Even today, you may be aware that Kite Gilead is going to run a head-to-head. even today you may be aware that kite gilead is going to run a head-to-head

Speaker 2: Yeah Yeah yeah

Speaker 1: have a different CD19/20 in development, and they're about a year behind us because it takes about a year to get these sites activated. We've been working on our program for well over a year. They're not allowing bridging therapy, and they're only randomizing patients to Yescarta. We're allowing randomization for the investigator to pick either Yescarta or Breyanzi. A little bit more real world, and we think that's going to be very much to our advantage. have a different CD19/20 in development, and they're about a year behind us because it takes about a year to get these sites activated. have a different cd19/20 in development and they're about a year behind us because it takes about a year to get these sites activated We've been working on our program for well over a year. we've been working on our program for well over a year They're not allowing bridging therapy, and they're only randomizing patients to Yescarta. they're not allowing bridging therapy and they're only randomizing patients to yescarta We're allowing randomization for the investigator to pick either Yescarta or Breyanzi. we're allowing randomization for the investigator to pick either yescarta or breyanzi A little bit more real world, and we think that's going to be very much to our advantage. a little bit more real world and we think that's going to be very much to our advantage

Speaker 2: Yeah. Given how the market share appears to have split out between Breyanzi and Yescarta, that may represent a competitive disadvantage for them in terms of enrollment accrual. You talked about the Kite product, right? I know in your opening statement you referenced a tandem binder that was engineered into ronde-cel. Kite uses this bicistronic binder. How do you think just that engineering difference alone gives you a leg up as you think about comparing and contrasting the two products in this setting? Yeah. yeah Given how the market share appears to have split out between Breyanzi and Yescarta, that may represent a competitive disadvantage for them in terms of enrollment accrual. given how the market share appears to have split out between breyanzi and yescarta that may represent a competitive disadvantage for them in terms of enrollment accrual You talked about the Kite product, right? you talked about the kite product right I know in your opening statement you referenced a tandem binder that was engineered into ronde-cel. i know in your opening statement you referenced a tandem binder that was engineered into ronde-cel Kite uses this bicistronic binder. kite uses this bicistronic binder How do you think just that engineering difference alone gives you a leg up as you think about comparing and contrasting the two products in this setting? how do you think just that engineering difference alone gives you a leg up as you think about comparing and contrasting the two products in this setting

Speaker 1: Yeah, I think the data are going to speak for themselves as time goes by. I have to speak in theoreticals. I think what typically is thought of is that a tandem CAR means there's one CAR expressed, so that's advantageous to the cell. If you have two CARs expressed, it's more metabolically difficult for the CAR to express two. In this case, in the case of Kite, they're expressing Yescarta for the CD19 component and then a CD20, a separate CAR. That is some metabolic stress. It's a little bit more difficult in manufacturing, isn't it, to make sure you get consistent expression of both over time? There's some school of thought that having these two different CARs, one with a CD28 costimulatory domain, may lead to more T-cell exhaustion, which would not be good for durability. Yeah, I think the data are going to speak for themselves as time goes by. yeah i think the data are going to speak for themselves as time goes by I have to speak in theoreticals. i have to speak in theoreticals I think what typically is thought of is that a tandem CAR means there's one CAR expressed, so that's advantageous to the cell. i think what typically is thought of is that a tandem car means there's one car expressed so that's advantageous to the cell If you have two CARs expressed, it's more metabolically difficult for the CAR to express two. if you have two cars expressed it's more metabolically difficult for the car to express two In this case, in the case of Kite, they're expressing Yescarta for the CD19 component and then a CD20, a separate CAR. in this case in the case of kite they're expressing yescarta for the cd19 component and then a cd20 a separate car That is some metabolic stress. that is some metabolic stress It's a little bit more difficult in manufacturing, isn't it, to make sure you get consistent expression of both over time? it's a little bit more difficult in manufacturing isn't it to make sure you get consistent expression of both over time There's some school of thought that having these two different CARs, one with a CD28 costimulatory domain, may lead to more T-cell exhaustion, which would not be good for durability. there's some school of thought that having these two different cars one with a cd28 costimulatory domain may lead to more t-cell exhaustion which would not be good for durability These are theoretics. We're going to have to see how the data play out. Right now, we are very pleased with the performance of our tandem CAR, both in terms of the complete response rates we're seeing and, very importantly, the durability and the safety profile. These are theoretics. these are theoretics We're going to have to see how the data play out. we're going to have to see how the data play out Right now, we are very pleased with the performance of our tandem CAR, both in terms of the complete response rates we're seeing and, very importantly, the durability and the safety profile. right now we are very pleased with the performance of our tandem car both in terms of the complete response rates we're seeing and very importantly the durability and the safety profile

Speaker 2: Okay. J&J recently announced- Okay. okay J&J recently announced- j&j recently announced- that it was discontinuing its CD19, CD20 dual CAR T program. Do you think that this reflects any read-through in terms of their interpretation or perspective of the competitive landscape or commercial opportunity, or do you think this was just probably an isolated asset-specific decision that the company made? that it was discontinuing its CD19, CD20 dual CAR T program. that it was discontinuing its cd19 cd20 dual car t program Do you think that this reflects any read-through in terms of their interpretation or perspective of the competitive landscape or commercial opportunity, or do you think this was just probably an isolated asset-specific decision that the company made? do you think that this reflects any read-through in terms of their interpretation or perspective of the competitive landscape or commercial opportunity or do you think this was just probably an isolated asset-specific decision that the company made

Speaker 1: Well, one can never know what goes on inside of Johnson & Johnson. I think obviously they said it was a business decision. I have to believe it did have to do with the competitive landscape, but maybe not in the way people think. We know that J&J licensed their product from China from a company known as AbelZeta. We know that they were having some trouble with dose finding because the dose used in China to present some very nice data was about 150 million cells. They'd already dropped back to about 75 million cells, which implies something was happening. Interestingly, they didn't show up at ASH with any new clinical data, which was sort of surprising, the big hematologic cancer meetings at the end of the year. They pulled out altogether. Well, one can never know what goes on inside of Johnson & Johnson. well one can never know what goes on inside of johnson & johnson I think obviously they said it was a business decision. i think obviously they said it was a business decision I have to believe it did have to do with the competitive landscape, but maybe not in the way people think. i have to believe it did have to do with the competitive landscape but maybe not in the way people think We know that J&J licensed their product from China from a company known as AbelZeta. we know that j&j licensed their product from china from a company known as abelzeta We know that they were having some trouble with dose finding because the dose used in China to present some very nice data was about 150 million cells. we know that they were having some trouble with dose finding because the dose used in china to present some very nice data was about 150 million cells They'd already dropped back to about 75 million cells, which implies something was happening. they'd already dropped back to about 75 million cells which implies something was happening Interestingly, they didn't show up at ASH with any new clinical data, which was sort of surprising, the big hematologic cancer meetings at the end of the year. interestingly they didn't show up at ash with any new clinical data which was sort of surprising the big hematologic cancer meetings at the end of the year They pulled out altogether. they pulled out altogether I think one of the things that we know we did was we went out very early with this head-to-head study. We got all the major sites agreeing to participate in our study. We put up our steering committee. Over time, we knew that J&J was going to these same sites and saying, "Oh, we want to run a study." They were told, "No. Well, we've already committed to Lyell, and we're working with Lyell in the study." We turned them down. It could be Johnson & Johnson doesn't like to be second, right? Or third. They like to be the leader, particularly in a marketplace like this. It's possible that they just got behind and decided that it wasn't worth it for them to be the third head-to-head trial ongoing. I think one of the things that we know we did was we went out very early with this head-to-head study. i think one of the things that we know we did was we went out very early with this head-to-head study We got all the major sites agreeing to participate in our study. we got all the major sites agreeing to participate in our study We put up our steering committee. we put up our steering committee Over time, we knew that J&J was going to these same sites and saying, "Oh, we want to run a study." They were told, "No. over time we knew that j&j was going to these same sites and saying "oh we want to run a study." they were told "no Well, we've already committed to Lyell, and we're working with Lyell in the study." We turned them down. well we've already committed to lyell and we're working with lyell in the study." we turned them down It could be Johnson & Johnson doesn't like to be second, right? it could be johnson & johnson doesn't like to be second right Or third. or third They like to be the leader, particularly in a marketplace like this. they like to be the leader particularly in a marketplace like this It's possible that they just got behind and decided that it wasn't worth it for them to be the third head-to-head trial ongoing. it's possible that they just got behind and decided that it wasn't worth it for them to be the third head-to-head trial ongoing I think we took a very aggressive strategy, and I think it paid off. For whatever reason, doesn't matter, this is great news for Lyell because it's one less significant competitor in the marketplace, and we think we're clearly in the lead at this point, and not by a small margin. The onus is on us to continue this aggressive execution and stay on track to have this major data update at the second half of this year and then get that BLA submitted next year. I think we took a very aggressive strategy, and I think it paid off. i think we took a very aggressive strategy and i think it paid off For whatever reason, doesn't matter, this is great news for Lyell because it's one less significant competitor in the marketplace, and we think we're clearly in the lead at this point, and not by a small margin. for whatever reason doesn't matter this is great news for lyell because it's one less significant competitor in the marketplace and we think we're clearly in the lead at this point and not by a small margin The onus is on us to continue this aggressive execution and stay on track to have this major data update at the second half of this year and then get that BLA submitted next year. the onus is on us to continue this aggressive execution and stay on track to have this major data update at the second half of this year and then get that bla submitted next year

Speaker 2: Okay. Any thoughts on what Allogene's trying to do with their ALPHA3 trial, where they're looking at cema-cel as consolidation therapy and in patients who are MRD positive, absent clinical progression, post frontline therapy, do you think that success for them in that study somehow impacts the market opportunity in the second line setting? Okay. okay Any thoughts on what Allogene's trying to do with their ALPHA3 trial, where they're looking at cema-cel as consolidation therapy and in patients who are MRD positive, absent clinical progression, post frontline therapy, do you think that success for them in that study somehow impacts the market opportunity in the second line setting? any thoughts on what allogene's trying to do with their alpha3 trial where they're looking at cema-cel as consolidation therapy and in patients who are mrd positive absent clinical progression post frontline therapy do you think that success for them in that study somehow impacts the market opportunity in the second line setting

Speaker 1: Well, I think any success in cell therapy is good. I'm always happy when cell therapy companies do well, like Arcellx being acquired because all boats float. I think in terms of threatening ronde-cel, no. I think this is an allogeneic product. They showed some futility data that in 24 patients, 12 in each arm, showed that they were able to achieve MRD negative status. They've got a ways to go. We didn't get any durability data. It wasn't the primary endpoint of the study, they've got a ways to go, for us, it's a small patient population. It's not going to take away the major percent of the population because when you look at, even if they're 20% or 25% of patients are MRD positive after frontline therapy, half of them get testing and get cema-cel. It's not a major drawback for us. Well, I think any success in cell therapy is good. well i think any success in cell therapy is good I'm always happy when cell therapy companies do well, like Arcellx being acquired because all boats float. i'm always happy when cell therapy companies do well like arcellx being acquired because all boats float I think in terms of threatening ronde-cel, no. i think in terms of threatening ronde-cel no I think this is an allogeneic product. i think this is an allogeneic product They showed some futility data that in 24 patients, 12 in each arm, showed that they were able to achieve MRD negative status. they showed some futility data that in 24 patients 12 in each arm showed that they were able to achieve mrd negative status They've got a ways to go. they've got a ways to go We didn't get any durability data. we didn't get any durability data It wasn't the primary endpoint of the study, they've got a ways to go, for us, it's a small patient population. it wasn't the primary endpoint of the study they've got a ways to go for us it's a small patient population It's not going to take away the major percent of the population because when you look at, even if they're 20% or 25% of patients are MRD positive after frontline therapy, half of them get testing and get cema-cel. it's not going to take away the major percent of the population because when you look at even if they're 20% or 25% of patients are mrd positive after frontline therapy half of them get testing and get cema-cel It's not a major drawback for us. it's not a major drawback for us I'm happy for them. I wish them the best of luck, but I don't think this is a threat to ronde-cel. I'm happy for them. i'm happy for them I wish them the best of luck, but I don't think this is a threat to ronde-cel. i wish them the best of luck but i don't think this is a threat to ronde-cel

Speaker 2: Okay. One more competitor question then. Okay. okay One more competitor question then. one more competitor question then

Speaker 1: Okay. Okay. okay

Speaker 2: I'll stop. Legend just announced that they're going to be presenting some preliminary data for a in vivo 19/20 product at a medical meeting sometime later this year. I'm sure you're going to get this question asked a lot, if not already, how do you just think about in vivo CAR T as an existential threat to autologous and even allogeneic cell therapy within the setting of oncology specifically? I'll stop. i'll stop Legend just announced that they're going to be presenting some preliminary data for a in vivo 19/20 product at a medical meeting sometime later this year. legend just announced that they're going to be presenting some preliminary data for a in vivo 19/20 product at a medical meeting sometime later this year I'm sure you're going to get this question asked a lot, if not already, how do you just think about in vivo CAR T as an existential threat to autologous and even allogeneic cell therapy within the setting of oncology specifically? i'm sure you're going to get this question asked a lot if not already how do you just think about in vivo car t as an existential threat to autologous and even allogeneic cell therapy within the setting of oncology specifically

Speaker 1: In vivo is very exciting. It's a new technology. Autologous CAR T-cell therapy has been around for a decade plus. We understand it a lot. We've worked hard to get this next generation CAR T-cell therapy. We are very excited about in vivo and interested in it as well. If I were going to say, does this threaten ronde-cel, I would say no, I think it's complementary because Legend's going to put out their data. What are they going to have to do to threaten ronde-cel? Three things. They're going to have to put up complete response rates or overall response rates that are 90%, complete response rates that are 76%, which is what we've presented, and more importantly, median progression-free survival of 18 months. They just dosed their first patient in the summer. In vivo is very exciting. in vivo is very exciting It's a new technology. it's a new technology Autologous CAR T-cell therapy has been around for a decade plus. autologous car t-cell therapy has been around for a decade plus We understand it a lot. we understand it a lot We've worked hard to get this next generation CAR T-cell therapy. we've worked hard to get this next generation car t-cell therapy We are very excited about in vivo and interested in it as well. we are very excited about in vivo and interested in it as well If I were going to say, does this threaten ronde-cel, I would say no, I think it's complementary because Legend's going to put out their data. if i were going to say does this threaten ronde-cel i would say no i think it's complementary because legend's going to put out their data What are they going to have to do to threaten ronde-cel? what are they going to have to do to threaten ronde-cel Three things. three things They're going to have to put up complete response rates or overall response rates that are 90%, complete response rates that are 76%, which is what we've presented, and more importantly, median progression-free survival of 18 months. they're going to have to put up complete response rates or overall response rates that are 90% complete response rates that are 76% which is what we've presented and more importantly median progression-free survival of 18 months They just dosed their first patient in the summer. they just dosed their first patient in the summer They're not going to be able to have that, plus safety. That's a lot of variables that have to be hit first time up at bat with a very new technology. Can in vivo get there? Maybe over time, but it's not going to be as soon as maybe people currently think it is. This is a study done in China. It's going to have to be repeated, even if it is the be-all end-all. I think where I sort of see in vivo being very important, autologous CAR is the gold standard, and our CD19/CD20, I think is putting up data best in class. We believe we're going to be able to improve access because the value proposition for patients and for providers is improving. In vivo CAR can extend that access. They're not going to be able to have that, plus safety. they're not going to be able to have that plus safety That's a lot of variables that have to be hit first time up at bat with a very new technology. that's a lot of variables that have to be hit first time up at bat with a very new technology Can in vivo get there? can in vivo get there Maybe over time, but it's not going to be as soon as maybe people currently think it is. maybe over time but it's not going to be as soon as maybe people currently think it is This is a study done in China. this is a study done in china It's going to have to be repeated, even if it is the be-all end-all. it's going to have to be repeated even if it is the be-all end-all I think where I sort of see in vivo being very important, autologous CAR is the gold standard, and our CD19/CD 20, I think is putting up data best in class. i think where i sort of see in vivo being very important autologous car is the gold standard and our cd19/cd 20 i think is putting up data best in class We believe we're going to be able to improve access because the value proposition for patients and for providers is improving. we believe we're going to be able to improve access because the value proposition for patients and for providers is improving In vivo CAR can extend that access. in vivo car can extend that access That's a great thing for patients and the field at large. Do I think in vivo first time up at bat is going to replace and threaten autologous CAR? Maybe, but I'd be surprised. That's a great thing for patients and the field at large. that's a great thing for patients and the field at large Do I think in vivo first time up at bat is going to replace and threaten autologous CAR? do i think in vivo first time up at bat is going to replace and threaten autologous car Maybe, but I'd be surprised. maybe but i'd be surprised

Speaker 2: Okay. Maybe the last few minutes we can switch gears to LYL273. This is the GC-C targeting CAR that you licensed last year. Very unique mechanism of action. Can you explain the rationale for adding a separate CD19 CAR along with the CAR that's targeting GC-C that's expressed on tumor cells? What does that buy you from a biological perspective? Okay. okay Maybe the last few minutes we can switch gears to LYL273. maybe the last few minutes we can switch gears to lyl273 This is the GC-C targeting CAR that you licensed last year. this is the gc-c targeting car that you licensed last year Very unique mechanism of action. very unique mechanism of action Can you explain the rationale for adding a separate CD19 CAR along with the CAR that's targeting GC-C that's expressed on tumor cells? can you explain the rationale for adding a separate cd19 car along with the car that's targeting gc-c that's expressed on tumor cells What does that buy you from a biological perspective? what does that buy you from a biological perspective

Speaker 1: CAR T-cell therapy in solid tumors is hard. A lot of CAR T-cell therapies have failed. They may have had a good target, but that was not sufficient. It's necessary, but not sufficient. Guanylyl cyclase-C or GC-C is a great target for metastatic colorectal cancer because it's upregulated in more than 95% of them. We know a target alone is not sufficient, and the inventor of this CAR realized that there were two main barriers that had to be overcome. One is we need more cell expansion, and two is we need some way to make the hostile tumor microenvironment warmer, more friendly to these CAR T-cells so they don't just rapidly exhaust and die. The concept is there's GC-C CAR expressed, this is a dual targeting product, and separate, this is a CD19 CAR expressed. CAR T-cell therapy in solid tumors is hard. car t-cell therapy in solid tumors is hard A lot of CAR T-cell therapies have failed. a lot of car t-cell therapies have failed They may have had a good target, but that was not sufficient. they may have had a good target but that was not sufficient It's necessary, but not sufficient. it's necessary but not sufficient Guanylyl cyclase- C or GC-C is a great target for metastatic colorectal cancer because it's upregulated in more than 95% of them. guanylyl cyclase- c or gc-c is a great target for metastatic colorectal cancer because it's upregulated in more than 95% of them We know a target alone is not sufficient, and the inventor of this CAR realized that there were two main barriers that had to be overcome. we know a target alone is not sufficient and the inventor of this car realized that there were two main barriers that had to be overcome One is we need more cell expansion, and two is we need some way to make the hostile tumor microenvironment warmer, more friendly to these CAR T-cells so they don't just rapidly exhaust and die. one is we need more cell expansion and two is we need some way to make the hostile tumor microenvironment warmer more friendly to these car t-cells so they don't just rapidly exhaust and die The concept is there's GC-C CAR expressed, this is a dual targeting product, and separate, this is a CD19 CAR expressed. the concept is there's gc-c car expressed this is a dual targeting product and separate this is a cd19 car expressed Here what you have is a CD19 CAR is engineered to release cytokines or supportive hormones, you can think of it as. CD19, you're like, "Whoa, that's a B-cell target." Yeah, intentionally. There is 1 day of lymphodepletion, so when this product is infused, B-cells remain. The cells hit the B-cells, they activate, they release cytokines. This jumpstarts cell expansion, and in particular, we get nice expansion of these, what we call doublet cells, which have both CD19 and GC-C, which can get into the tumor with secretion of cytokines and warm up that tumor microenvironment. Then the largest number of cells are GC-C alone. They get in and kill the tumor. We've been seeing response rates across two dose levels in the 50% range. It's an active CAR. This novel mechanism, we think, is really something that's not been studied before. Here what you have is a CD19 CAR is engineered to release cytokines or supportive hormones, you can think of it as. here what you have is a cd19 car is engineered to release cytokines or supportive hormones you can think of it as CD19, you're like, "Whoa, that's a B-cell target." Yeah, intentionally. cd19 you're like "whoa that's a b-cell target." yeah intentionally There is 1 day of lymphodepletion, so when this product is infused, B-cells remain. there is 1 day of lymphodepletion so when this product is infused b-cells remain The cells hit the B-cells, they activate, they release cytokines. the cells hit the b-cells they activate they release cytokines This jumpstarts cell expansion, and in particular, we get nice expansion of these, what we call doublet cells, which have both CD19 and GC-C, which can get into the tumor with secretion of cytokines and warm up that tumor microenvironment. this jumpstarts cell expansion and in particular we get nice expansion of these what we call doublet cells which have both cd19 and gc-c which can get into the tumor with secretion of cytokines and warm up that tumor microenvironment Then the largest number of cells are GC-C alone. then the largest number of cells are gc-c alone They get in and kill the tumor. they get in and kill the tumor We've been seeing response rates across two dose levels in the 50% range. we've been seeing response rates across two dose levels in the 50% range It's an active CAR. it's an active car This novel mechanism, we think, is really something that's not been studied before. this novel mechanism we think is really something that's not been studied before It's very unique. It's very next generation. I think that's why we're seeing the activity that we are. It's very unique. it's very unique It's very next generation. it's very next generation I think that's why we're seeing the activity that we are. i think that's why we're seeing the activity that we are

Speaker 2: Okay. I know you've guided to having a couple of incremental clinical updates from this program later this year. What should we be expecting to see in conjunction with each of those disclosures? Okay. okay I know you've guided to having a couple of incremental clinical updates from this program later this year. i know you've guided to having a couple of incremental clinical updates from this program later this year What should we be expecting to see in conjunction with each of those disclosures? what should we be expecting to see in conjunction with each of those disclosures

Speaker 1: We're in the first half coming soon, we're going to have an update on the program. A lot of that is going to focus on safety because one of the side effects of this product is some diarrhea, and there was one patient who did get a pretty significant colitis that required some significant immunosuppressive therapy. The patient actually died from an infection. The colitis was controlled but got a subsequent infection. When he died, he had an autopsy. There was no evidence of disease. Again, this is an active CAR, but we need to show that we can manage the diarrhea. After this case, a significant prophylactic regimen was put in place with a safety management plan. We're in the first half coming soon, we're going to have an update on the program. we're in the first half coming soon we're going to have an update on the program A lot of that is going to focus on safety because one of the side effects of this product is some diarrhea, and there was one patient who did get a pretty significant colitis that required some significant immunosuppressive therapy. a lot of that is going to focus on safety because one of the side effects of this product is some diarrhea and there was one patient who did get a pretty significant colitis that required some significant immunosuppressive therapy The patient actually died from an infection. the patient actually died from an infection The colitis was controlled but got a subsequent infection. the colitis was controlled but got a subsequent infection When he died, he had an autopsy. when he died he had an autopsy There was no evidence of disease. there was no evidence of disease Again, this is an active CAR, but we need to show that we can manage the diarrhea. again this is an active car but we need to show that we can manage the diarrhea After this case, a significant prophylactic regimen was put in place with a safety management plan. after this case a significant prophylactic regimen was put in place with a safety management plan We're going to be updating on the next round of patients that were treated with that safety management plan, and to give investors an idea if we can control and manage appropriately the diarrhea. In the back half, we'll have a more fulsome update at a medical conference, where we'll be giving outcomes data as well. We're going to be updating on the next round of patients that were treated with that safety management plan, and to give investors an idea if we can control and manage appropriately the diarrhea. we're going to be updating on the next round of patients that were treated with that safety management plan and to give investors an idea if we can control and manage appropriately the diarrhea In the back half, we'll have a more fulsome update at a medical conference, where we'll be giving outcomes data as well. in the back half we'll have a more fulsome update at a medical conference where we'll be giving outcomes data as well

Speaker 2: Okay. You've suggested that peak capacity at your facility for ronde-cel, I believe, is around 1,200 doses a year. How do you accommodate 273 into your manufacturing plans? Are you tech transferring that in? What are your options to scale capacity for each of these products? Okay. okay You've suggested that peak capacity at your facility for ronde-cel, I believe, is around 1,200 doses a year. you've suggested that peak capacity at your facility for ronde-cel i believe is around 1,200 doses a year How do you accommodate 273 into your manufacturing plans? how do you accommodate 273 into your manufacturing plans Are you tech transferring that in? are you tech transferring that in What are your options to scale capacity for each of these products? what are your options to scale capacity for each of these products

Speaker 1: That's a great question. We do have our own manufacturing facility. It's state of the art. It's all paperless. We are running right now for ronde-cel, our commercial manufacturing process, and we can manufacture more than 1,200 doses per year, which can get us well into launch. We are transferring in this GC-C CAR program. It's very automated, so it's sort of made on the CliniMACS Prodigy, and it's quite easy and standard to run. For the time being, we can do both, and again, we can launch ronde-cel without difficulty. Over time, we'll need more capacity, more space, but again, that's a great problem for us to have, and it's not a near-term capital requirement. We can get far into launch before we need to go there. That's a great question. that's a great question We do have our own manufacturing facility. we do have our own manufacturing facility It's state of the art. it's state of the art It's all paperless. it's all paperless We are running right now for ronde-cel, our commercial manufacturing process, and we can manufacture more than 1,200 doses per year, which can get us well into launch. we are running right now for ronde-cel our commercial manufacturing process and we can manufacture more than 1,200 doses per year which can get us well into launch We are transferring in this GC-C CAR program. we are transferring in this gc-c car program It's very automated, so it's sort of made on the CliniMACS Prodigy, and it's quite easy and standard to run. it's very automated so it's sort of made on the clinimacs prodigy and it's quite easy and standard to run For the time being, we can do both, and again, we can launch ronde-cel without difficulty. for the time being we can do both and again we can launch ronde-cel without difficulty Over time, we'll need more capacity, more space, but again, that's a great problem for us to have, and it's not a near-term capital requirement. over time we'll need more capacity more space but again that's a great problem for us to have and it's not a near-term capital requirement We can get far into launch before we need to go there. we can get far into launch before we need to go there

Speaker 2: Okay. Okay. okay

Speaker 1: I think we can do both within our facility. I think we can do both within our facility. i think we can do both within our facility

Speaker 2: Okay. Just lastly, speaking of capital requirement, what is the current balance sheet, and what does that allow you to execute on here as you go forward? Okay. okay Just lastly, speaking of capital requirement, what is the current balance sheet, and what does that allow you to execute on here as you go forward? just lastly speaking of capital requirement what is the current balance sheet and what does that allow you to execute on here as you go forward

Speaker 1: The great news for us is we have, as we've just spoken about, some data-rich catalysts coming up here in the next period of time. We have, as of our Q1 filing, we had $261 million in cash, and that gets us through Q3 of next year and through these catalysts, including the pivotal data. The great news for us is we have, as we've just spoken about, some data-rich catalysts coming up here in the next period of time. the great news for us is we have as we've just spoken about some data-rich catalysts coming up here in the next period of time We have, as of our Q1 filing, we had $261 million in cash, and that gets us through Q3 of next year and through these catalysts, including the pivotal data. we have as of our q1 filing we had $261 million in cash and that gets us through q3 of next year and through these catalysts including the pivotal data

Speaker 2: All right. Well, we're out of time, Lynn. I really appreciate it. That was great. Thanks everyone for listening. All right. all right Well, we're out of time, Lynn. well we're out of time lynn I really appreciate it. i really appreciate it That was great. that was great Thanks everyone for listening. thanks everyone for listening

Speaker 1: All right. Thank you. All right. all right Thank you. thank you