Lyell Immunopharma, Inc. ($LYEL)

Hello, everyone. My name is Mitchell Kapoor. I'm a senior biotech analyst at H.C. Wainwright and the covering analyst for Lyell. Today, I have the pleasure of welcoming Lynn Seely, the CEO of the company. Today, we're going to have a fireside chat, talk a lot about the CD19/20 space, what they have going on in colorectal cancer and anything else that Lynn thinks would be important to discuss.

So maybe with that, you could just start by giving those who are not up to speed with the story, a brief overview of the company and the current initiatives and maybe just an overview of the data that we've seen so far.

Great. Well, thank you for having me here today. I will be making forward-looking statements for the record, so consult our website and securities filings. For those who aren't as familiar with Lyell, we are a cell therapy company developing next-generation cell therapies, both for hematologic malignancies as well as for solid tumors. And we have 2 lead programs in the clinic, both targeting large markets. The first is our -- is ronde-cel, our CD19/CD20 dual-targeted CAR, which we're developing really to become the standard of care in the $3 billion CAR T cell CD19 marketplace that's established today in large B-cell lymphoma. And then secondarily, we have a program for metastatic colorectal cancer, which is a very novel CAR, which, we think, is a really, obviously, large market surging in young people. And CAR T cell therapy for young patients is really just a great fit. So these programs are both in the clinic. The lead ronde-cel is, as I said, a dual-targeting CD19/CD20 CAR T cell therapy. We are currently in 2 pivotal trials. The first is in the third or later line, and this was a program that we presented data on last year 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. And these are data that really set the CD19/CD20 apart from the CD19. Based on this, we have a pivotal trial ongoing, which we call the PiNACLE study, which we expect to have a significant data update in the second half of this year. And then we intend to present the pivotal data next year with BLA submission next year. So this program is barreling forward in the third or later line. We also have a first-of-its-kind CAR T cell therapy head-to-head trial, which we initiated several months ago, actively enrolling patients, which we think is really -- it's in the second line and is going to just further set this program apart. So we're really excited about the progress we're making in the ronde-cel program. And then we also have this colorectal program, which is in clinical trials in the U.S. This program was licensed from a company who initially developed it in China, but then brought it to the U.S. and has replicated, to a great extent, the data seen in China in the U.S. And so we're continuing this program forward in a way. It's a very novel CAR. We think something that is potentially transformative for the company. And then maybe lastly, I'd be remiss if I didn't tell you that Lyell has its own manufacturing center. So this is a state-of-the-art facility where we can launch commercially from this facility and manufacture up to 1,200 doses annually. So it really gets us nicely into launch. So we do have control of our own destiny, which is important.

Excellent. So just starting with ronde-cel, CD19/20 CAR T space. We've got a lot of investor interest in that out of ASH and all the way since. A lot of competitors have emerged. So maybe to set the stage before we jump into a little bit more finer questions is how do you view ronde-cel in the competitive landscape? Of course, one of the things that sticks out to us is the median PFS of 18 months and the geography of where that has been established. But maybe you can just kind of help us understand the competitive differentiation in the emerging class of CD19/20 when, arguably, you're leading the space.

Yes. Well, thank you. It's a big question. So this field is moving rapidly, as people know, and I'm very proud to say Lyell is in the lead. And when we acquired this product at the end of 2024, people weren't even really that confident that the 19/20s were going to be important in the field. And fast forward to the spring of 2025, at the premier lymphoma meetings that are held in Lugano, Switzerland, 3 companies put up data for their CD19/CD20 CARs. There was Lyell, there was Johnson & Johnson, and there was Kite Gilead. And all 3 were showing nice data that appear to be clearly better than the CD19 CARs, which was important. But what I'd like to say is Lyell has continued to advance forward very rapidly. As I said, we initiated 2 pivotal trials. We selected our recommended pivotal trial dose and have moved rapidly forward presenting at ASH in 2025 this really strong data that I just told you about. In the meantime, Johnson & Johnson, you may have heard, has just recently stepped out of the CD19/20 race, and we can just talk a little bit about that. So they didn't present any data at ASH 2025, which was surprising -- any clinical data, I should say -- which was surprising to us. And then Kite Gilead, who's also in this race with a different type of CAR construct, actually discontinued the program that they were initially moving forward with and opted for a different manufacturing process. That set them back. So they're coming, they're still in the race, but with several months, if not a full year or more, behind us. So I think what I'm very proud of is Lyell has emerged with a strategy that really is putting us in the lead with a very strong program, both with respect to the clinical outcomes that we're observing, the safety profile as well as a very reliable manufacturing process.

Thank you. Yes. Very interesting. And recently, as you mentioned, J&J discontinued its ex vivo CD19/20 CAR T along with its CD19 mono CAR T as well. Just curious what you think that signals for the field, if anything, and maybe help us understand how you view their data. I think it was generated in China. They had a 5-year median PFS. Anything that we can learn from a competitive lens that frames where ronde-cel operates today and if that has any signal for the class in general?

Sure. I think there's a lot of important messages there. The first thing I would say is this is great news for Lyell. And I think it just takes out a competitor, which is always important, obviously, not only for the recruitment time lines and clinical trials, but more importantly, for the commercial marketplace. And so the big question is, why did they drop out? Did they have some big strategic insight into the way the market was developing? Or I would put forth, quite frankly, I'm very proud of Lyell's strategy, right? We moved, we moved aggressively. We picked our dose. They were having a hard time finding their dose. If you look back at the data they initially presented, they had -- they looked at 150 million cell dose. They looked at a 75 million cell dose, and it wasn't quite clear what direction they were going. They didn't present any new clinical data at ASH, which was surprising. In the meantime, we barreled forward. And so if you think about a company like J&J, if they're not going to be first-in-class with a large market, they're generally not one to play. And it's possible that Lyell beat them, and they didn't want to be third after Lyell and Kite Gilead. And it's also important to note that the constructs between the 2 programs were highly similar. Prizlon-cel or the J&J product originated in China from a company called AbelZeta that began developing this after the originator of the Lyell product, Yvonne Chen, patented and published her data and her structure. And then they came out with this data from China, which was very compelling. AbelZeta came out with this data from China that was very compelling. One of the lessons that's very important to appreciate is that in lymphoma and, of course, other cancers as well, who you enroll in your patients, what the demographics and the disease characteristics are do impact outcomes substantially. And so in that trial initially done in China, if you look at it carefully, the median age of patients was 55. Well, large B-cell lymphoma is a disease of the elderly. If you look at the median age in our trials, the median age is 65, a decade later, with 20% of patients over the age of 75. So that was surprising. The other thing that was surprising, if you look at something like performance status, the overall health of the patient, it's captured in something called the ECOG performance status. About 65% of their patients were normal. You might see only 30% of patients having 70% being elevated or decreased performance status in the [indiscernible]. So those are sorts of things that would impact the outcome. So I think at this point in time, what I'm really proud of is that, I think Lyell is moving forward. We've been moving forward consistently with the same dose treating patients. Our data have been consistent over time. And we're really looking forward to providing a significant data update on this program, data from the pivotal trial in the third or later line in the second half of this year.

Great. Yes. And I'm just going to maybe jump around and talk us a little bit because it's related. But with Kite, you mentioned so with J&J, one interpretation could be that maybe potentially you were beating them on durability and other metrics and that they decided, hey, we're not going to compete. Do you -- is that what you think happened with Kite as well when they move from 363 to 753? What is your interpretation of them stepping back from 363?

Well, obviously, we don't know what goes on inside of companies, but taking a careful look at the data they presented at the Switzerland Lugano lymphoma meetings, they had a 46% rate of Grade 1 or 2 ICANS. That means about half of their patients were developing ICANS, which is not a great product profile. And if you think about the problems they're having with YESCARTA to date with their neurotoxicity, they probably didn't want to get into that same situation. So they moved to a different manufacturing process, I have to suspect, obviously, I don't know, to get that ICANS rate lower. What we do know about their construct is it's very different from ours. We have a single CAR express that binds both CD19 and CD20. So it's in a single CAR, and it's full potency at either CD19 or CD20. They express 2 CARs on T cells. And so one is YESCARTA and the other is CD20. And so these are going to be a test of which is better, a bicistronic CAR or a very well-designed full-potent tandem CAR. And so we'll see. But I have -- that's what they're moving forward now.

Great. Okay. And then so on J&J's construct that has been discontinued prizlon-cel. That was a potential benchmark for durability. I think it was up in the air for folks since the data hadn't been replicated yet. But now that, that's not even really a question, what do you view -- who do you view as the main competitor? And what do you think the right bar is in third line, I guess, to start off since that is where most, I think, will start as kind of the later line setting for J&J?

Yes. So I think the bar is our key competitors which are Breyanzi and YESCARTA. Our objective and from day 1 has been to bring next-generation CAR for large B-cell lymphoma. And the first generations were transformative, but now we're ready for the next step, right? And so we really are looking to replace them. And so what is the bar, they set, in the third or later line. They have about 70% overall response rate, 50% complete response rate and 6 to 7 months median progression-free survival. We're coming with a 93% of our response rate, 76% complete response rate with a median progression-free survival of 18 months. So substantially not -- I mean it's clear data. It's not -- you don't have to wonder about is that really better. That's pretty clear. With a safety profile where we have seen no Grade 3 or higher cytokine release syndrome in our program and that our ICANS rate that we reported at ASH is less than 5%. So a very nice product profile appropriate for outpatient administration.

Great. Okay. And then for Kite's newer construct, 753, obviously, they took a step back and it's going to take them a while to show durability. But the durability on the first construct was okay. And they didn't have mPFS yet, and you all do. So you're still in the lead, and now you're in the lead by a larger margin. But if they continue to show, let's say, similar early CRs and durability of those CRs, do you view them as a competitor? Or do you think that lead is very important? How do you see them as a competitor? Obviously, YESCARTA, Breyanzi, definitely you're -- I think it's -- a lot of folks feel like the CD19/20s are trumping those at this point. But how do you view these emerging?

Well, I mean, first of all, I think it's very validating that somebody who's in the space also agrees that the CD19/20s are going to replace YESCARTA and Breyanzi. I think, of course, they will be a competitor. But one of the things that, I think, we have done and done very well is we've got this third-line program that we're taking for approval. And remember, the primary endpoint of that study is overall response rate. And I just told you our overall response rate is 93%. So that bodes very well for us to getting approval. And getting out first and replacing the CD19 CARs is very important to us. We -- because think about it, we know these physicians. CAR T cell prescribers are very much data-driven. They will switch products based on better safety or better efficacy, and we intend to bring both. So if we can get them to switch to us, then whoever comes second is going to have to supplant us, but there's not very much headroom left, right? The efficacy is already very good. The safety is already very good. So to be better is going to be hard. So being first is actually, I believe, in this particular situation, quite important. And then the other thing we've done is we have a very elegant design for a head-to-head study, which they are not matching. And I think I heard from many, many of the investigators and leaders in the space that they really like our head-to-head study design because we allow a real-world investigator's choice that physicians are able to select either YESCARTA or Breyanzi as the comparator, whereas in the Kite study, they're only comparing against YESCARTA.

Okay. Wonderful. And I think the final competitor that I have yet to bring up, it's much earlier, but people are really interested in this. In vivo CD19/20 CAR T Legend has a construct, and we may hear more. We're going to hear more soon at a major medical meeting midyear. How do you view in vivo versus your ex vivo approach? And obviously, all the things we talked about, the little headroom to beat where you're at. Some folks say, with in vivo, there may be an off-the-shelf approach and you can maybe be a little bit more equivalent or the bar is a little lower for them. Wondering how you view in vivo broadly versus ronde-cel?

Sure. So the field is very excited about in vivo CAR, as are we, right? This is an exciting new technology. But as you pointed out, it's very early. And so what is in vivo CAR going to have to bring to the table to be a threat to ronde-cel, right? And so 3 things. It's got to have the same CR rates; it's got to have durability; and its safety. So you have to assume that the very first CD19/20 in vivo CAR is going to come out with all 3 of those variables on par at first shot to be a threat to ronde-cel. And while that might happen, I think the probability is it's going to take a while, right? And in the meantime, the Legend program, which is coming out, we're all looking forward to seeing the data, is being developed in China. So they're going to have to repeat that, right? And durability, as we know, takes some time. I've just told you our median progression-free survival is 18 months. So we feel very confident in our position with ronde-cel. We believe that autologous CAR is the standard of care and will continue for CAR T cell therapy. Where in vivo is exciting, as you say, it can broaden access, right, that it can be available for patients who can't get the standard of care, but in terms of a threat to ronde-cel, it's going to take some time, and I think we're in a great position. And I would also say that we believe we're going to be able to improve access with ronde-cel. And I say that because the value proposition is changing. If you think about it, the safety profile is much better. So you can be treated as an outpatient. It's much easier for community hospitals or centers to manage. Number two is the benefit is better. So before you -- in the third line, for example, you had a flip of a coin, 50% chance of going into remission. Now we're saying 75%, right, much higher. And so with that value proposition for patients and for providers, I think that's also going to help with the access for autologous CAR.

Great. Okay. And so moving from third line to second line, you have the head-to-head trial, which is super important. As you mentioned, it's DLBCLs. It's very hard to compare cross trial because of the patient characteristics. What result would be sufficient? What result would be positive? Help us walk through the scenarios. And I think the obvious answer is just beating the competitor, right? But if you beat just by like 1% CR, it's not -- is it a big deal, right? Because safety is better. Like walk through maybe some scenarios how we should interpret second line.

Well, this is the gold, gold standard randomized controlled superiority trial. So the p-value is going to determine success, right? It's a benefit that, I think, we're going to be randomizing patients. They're going to be apples-to-apples with stratified for risk. And so that if we show better event-free survival, which is the primary endpoint that's statistically significant, that's going to be absolutely fantastic and sufficient and something that we think is very probable based upon the data that we have observed to date. And then there is safety, right? Because remember, physicians, these prescribers make decisions not only on the efficacy benefit, which is the most important, but also on the safety profile. So we have 2 opportunities really to demonstrate the full potential of our product.

Great. Okay. And from -- when we're thinking about the second-line opportunity versus the third-line opportunity, I think it would be helpful for the audience to understand how do you view the third line and the second line in terms of contribution to the commercial opportunity for Lyell. I think some folks previously had thought, like, well, they need to get to second line, right? So help us understand, what if it's a third-line therapy and that's all you're pursuing? And what's the additional benefit of getting into second line? How do we think about that?

We think this is something that a lot of people are missing. And we know from series that have been published at Memorial Sloan Kettering from our own experience, from claims data, that more than 50% of patients have already experienced 2 lines of chemotherapy before they undergo apheresis. And so we know that the intent of CAR is cure. And so if you're not getting cured by that second line, meaning going into complete response or a very good partial response, that is, in essence, an on-label third-line patient. So we think that there are 6,000 to 7,000 patients eligible for CAR in the third line. Being first with this third line with the BLA submission expected next year, we think this is a substantial opportunity for us. And then remember, our footprint for our head-to-head trial, we've got sites all over the country enrolling patients on to ronde-cel and get experience with the product now as we're recruiting this head-to-head trial. So we think this combination, this strategy bodes very well for the launch of this product.

Could you also help just clarify that third line? Like who are those third-line patients? Sometimes physicians don't even realize right now that maybe they have a third-line patient and it's a second-line patient. We had discussed a little bit about that, but that was super interesting to me. I think we could share with the audience so they can understand that this is maybe even bigger opportunity.

Yes. So doctors don't count lines right now. CARs are approved in both the second and the third lines. And so NCCN guidelines say, give CAR in the second line. So there is intention to treat in the second line. But what happens is if you're in the community and you progress on frontline therapy, about 50% of the time or more, you get started on another line of chemotherapy as you get referred in and get that medical appointment for apheresis. And so that's the second line. If you don't have a CR to that, if you don't have a very good partial response to that, you're a third-line patient. And so that's what we're seeing. And so that's why we know that the potential market for this is much bigger than many people expect.

Excellent. Okay. And last on ronde-cel before we move on. Can you help us understand where the CD62L enrichment is doing the work and just a little bit of the differentiation of the construct?

Yes. This is very much our secret sauce, and I think this is something we do during manufacturing. It's a very short cell selection process where we are enriching our product for naive, more fit central memory and naive T cells, which really have multiple purposes, but I like to think of it primarily is giving that duration of response. They persist. They don't get exhausted and die off as quickly as those more differentiated cells do. And then, of course, it also helps with what we call the softer safety profile.

Okay. Great. And then moving to CRC. LYL-273 is showing activity that's really unprecedented for cell therapy in solid tumors. What gives you the most confidence that the signal that we've seen so far is real and reproducible as a solid tumor CAR T? And just help us understand how beneficial the data look in later-line colorectal cancer where the options are so low.

Yes. The options are really sad, quite frankly. They're sort of frontline therapy and then a whole bunch of stuff that doesn't work, quite frankly, or doesn't work well. And I think what we're seeing is an active CAR T cell therapy for metastatic colorectal cancer. Why can I say that? Because we're seeing patients having responses and even patients with -- we have a patient, for example, that we've presented data publicly with that is now 2 years out from her CAR T cell therapy, ctDNA-negative, right? So no evidence of disease at this point. So we're seeing very nice response rates. We know it's an active CAR. And so the onus is on us now [ is ] to move the development forward as quickly as we can. And so why am I confident? Because this CAR design answers a couple of the key barriers in solid tumor, right? One is the fact that we get the cell expansion that we need because we have partnered our CAR with CD19 CAR, which is a really unusual novel design, which helps get that cell expansion that we need to get the GCC CARs into that hostile tumor microenvironment. And then the other thing we've done is engineer the CD19 CAR to release cytokines or these, sort of, supportive hormones, basically, is a simple way to think about these cytokines, that they actually open up the hostile tumor microenvironment by supporting these CARs inside the tumor and allowing them to expand and kill. So it is this novel mechanism, coupled with the activity that we're seeing in patients in the U.S. that is giving us that confidence.

Excellent. We've covered a lot of ground today. I think, to close, I would love to have you recap the catalysts ahead. I think this is truly an eventful year for the company. So maybe help us set the stage for those who now have Lyell on their watch list for 2026 and 2027.

Thank you. No, we're super excited about the upcoming time frame. We really think we're in a great position to have tremendous value creation. We have a substantial update on the pivotal trial in third-line PiNACLE coming in the second half of this year, which is, I think, going to be an important update. We have the pivotal data coming next year as well as BLA submission from that program. And then in the colorectal program, there's going to be 2 updates. The first, in the first half coming soon, is going to be a safety update, largely to show that not only do we have an active CAR that we can treat these patients with a good safety profile. And then in the back half of the year, a presentation at a medical conference we hope where we can have more broader clinical outcomes as well.

Excellent. Thank you so much, Lynn. Thank you to the Lyell team, and thank you to all the investors that joined us today.

Thanks, Mitchell.