Good morning everyone. My name is Daina Graybosch. I'm a senior equity research analyst here at Leerink Partners. I cover mostly immuno-oncology companies, and in that, I'm really thrilled to be hosting the CEO of Lyell, Lynn Seely. We were just talking, cell therapy companies still dedicated and focused on oncology indications. I think we'll start. You had some news this morning, so maybe everybody's been busy, they haven't seen it. You could just give us a quick overview of the news, and then we'll get into the programs.
Sure. I think everybody knows Lyell Immunopharma is focused on next generation CAR T-cell therapies for large B-cell lymphoma, and we also have a new novel CAR T-cell program for metastatic colorectal cancer. Today, we had two big news items. First and foremost, we hired our new Chief Financial and Business Officer, Smital Shah, who's joining us with significant experience in the financial and business development areas. We also announced the taking the hitting of a clinical milestone and allowing us to take a second $50 million tranche from a pipe that we did in July 2025 at a price of $25.61. A big day for Lyell all around.
That's great. Let's talk about, since we only have 30 minutes, the first program, ronde-cel. Is that how you say it, ronde-cel?
Ronde-cel, yes.
Which is your bispecific CD19, CD20, auto CAR T. One, can you just tell us more about ronde-cel and why you believe it has a best in class profile?
Yes. We believe ronde-cel is going to be first in class and also has a best in class profile. It is a dual targeted CD19, CD20 CAR T-cell. It was really meticulously designed to have full potency at either CD19 or CD20. It's a tandem CAR. It was designed very specifically to bring more complete responses because some malignant B-cells, for example, don't have CD19 or express low levels of CD19, and so patients don't go into complete response with CD19 CARs. It also, because they're two antigens, it's much more difficult for a cancer to escape from two antigens than it is to one. We expect that dual targeting also to help with longer persistence and duration of response. Finally, the other very special thing we do is in our manufacturing, where we do something called CD62L selection or enrichment.
This is to make our cell product very high in naive and central memory T-cells, which have been really shown retrospectively in trial to help with outcomes for patients. We at Lyell are very much excited that we have two pivotal clinical trials ongoing for ronde-cel. We believe we're going to be first to the market and then with a best in class profile, both with high complete responses, durable responses, and then really a safety profile, which is very amenable to outpatient administration.
Let's talk more about the differentiation, the CD62L, because that's quite distinct from your competitors. What gives you confidence in that approach versus a lot of the other competitors have gone through the shorter manufacturing or Kite, which is, you know, the other company that certainly had to have signed like you, a second line. Maybe they're the most similar competitor so far in terms of their clinical strategy. They employ this split co-stimulation. The CD62L versus shorter co-stimulation.
Yeah. There's a lot packed in there. I would say, Lyell has already initiated our pivotal head-to-head trial. We treated the first patients in February, we're off and running with many studies, been active and more to come. We're really excited about that. Our CAR construct and our cell manufacturing is quite unique. As I said before, we very specifically wanted to have a tandem CAR. This was meticulously engineered, if you're gonna have a tandem CAR, which means there are two binders on a single CAR, it has full potency at either CD19 or CD20. This is actually very good for the cells. It's much, it's a much lower, shall we call it metabolic stress for the cells to express one CAR.
It's much easier from a transaction perspective and a manufacturing perspective to get nice, consistent expression of a single CAR as opposed to trying to express two CAR. This was very intentionally designed by Dr. Yvonne Chen at UCLA to be a tandem CAR and not two separate CARs, to get better transaction, higher expression of both the CAR on the cells compared to what might happen if you tried to express two. We think the design of the tandem CAR is really exceptional and gives us great advantage there. This is coupled, and has been from the beginning with the CD62L selection.
We had an oral translational presentation at ASH, where we demonstrated that this CAR has three times higher cell expansion, in patients, both Cmax and AUC, so persistence, than axi-cel or liso-cel, for example. We believe this has a lot to do with the CD62L expression. We were also able to show for the first time persistence. We can take CAR T-cells from the peripheral blood of patients two months after they've been infused, co-culture them ex vivo with cancer cells and show cancer cell killing. Nobody else has ever been able to show that to our knowledge because you can't get enough cell expansion and enough persistence.
Interesting. Cancer cells you took from the patient initially or just like cancer cell lines?
Just cancer cell lines, yes. There's far infusion, so they're not only present, they are functional. This is, we believe, the real advantage of the ronde-cel design.
Clinically, it's really hard to compare the outcomes of these studies. It's really hard. We have yours, we have the Kite one, we have one from J&J, cilta-cel, then we have the sort of home brew Miltenyi version. All the designs are a little bit different, which we find, Bill, my associate and the team and I, we've tried really hard, and it's almost impossible. What outcomes do you look at to give you confidence that this translational profile is translating to a great clinical profile compared to the others?
Yeah. I would say first and foremost, outcomes in patients with large B-cell lymphoma treated with CAR are very much impacted by the patient demographics.
Yeah
And disease characteristics. You have to know who you're treating before you can start to look at outcomes. Really a deep understanding of the types of patients and their disease is important. Most of the data are out there are single-arm studies. If you really understand who's enrolled, then you can get a good idea about what you're looking at. We are really competing against CD19 CARs, right? That vials in the, in the lead with ronde-cel, our intention is to displace CD19 CARs.
Yeah.
If you look at the single-arm data that they got approved with in the third or later line, we have a very competitive profile. Our overall response rates is 93%, data we presented at ASH, versus the 70% by the CD19 CARs. Our complete response rate, 76% versus 70%. Really importantly, the median progression-free survival we presented at ASH last year was 18 months in the third or later line, compared to seven months with the CD19 CARs. This gives us great confidence as we move into these two pivotal trials, the single-arm study and the third or later line. In the second line, we also are very confident because historically with Breyanzi and axi-cel, the third line data translated very effectively into the second line data.
When you look at our second line data, it really is the data that experts in the field get the most excited about because we enrolled the hardest to treat patients in the second line. These are patients that don't even respond to first-line therapy, known as primary refractory disease patients. If you kinda look in the literature, you don't see much from Breyanzi or YESCARTA on those patients because they're so difficult to treat. They were reported in the pilot study for Breyanzi, the primary refractory subset, with a 42% complete response rate. In our primary refractory patients, we showed a 61% complete response rate. Again, much better. We know these patients don't do well, and yet in our trial, they are doing well.
We have great confidence, not only because of what's known about the biology, but also because of the emerging data profiles.
You said it's important to know, like, the patient you're treating. I find it hard to compare to the initial third line studies of the CD19 CAR T, 'cause that's a long time ago. Like, what kind of patients were being put on those studies versus the patients that are being put on your third line study? Do you think there's a trend towards better or worse prognosis? There's an impact of all the physicians know how to use CAR Ts now. Could your, you know, indirectly better CR rate simply be a difference of who those patients are and better treatment at the centers?
Yeah. Of course, the problem with single-arm studies, one of the reasons we are leaving no doubt, we are running the pure test of the head-to-head study in the second line. We will know that answer full stop. Be that as it may, every sign we have is that our drug, our product is performing very well in the third or later line. I mean, these aren't small benefits, right? These are large benefits that we're seeing over the third line patient. Remember, if you go back to those Breyanzi and axi-cel, YESCARTA trials, they didn't enroll anybody over the age of 75. We have no upper age limit. We're allowing patients to come in. We've treated 87-year-olds with good outcomes.
This tells you that we're treating if anything, because physicians are so much more comfortable with CAR today, sicker patients than were treated back then because we know how to treat the side effects. The other thing is in the YESCARTA trials, they didn't allow bridging therapy.
Yeah.
Right? That if you were progressing so rapidly you couldn't wait for CAR, you couldn't come on their trials. Well, we allow bridging therapy because that's what's done in the real world. When you look at the patients enrolled in our trial, you'll find that they are quite comparable, and we believe in some ways even sicker because they're older.
Yeah. Even though physicians are more used to it, that's expanded this population. You have these two dynamics overall.
Mm-hmm
... confidence.
Mm-hmm.
Can you talk about bridging therapy? That's been very interesting 'cause Kite always only allowed steroid and I think targeted radiation, whereas you did see some bridging therapies allowed in the BMS and Novartis allowing it.
We are.
How important do you think bridging therapy is? Is that gonna be differentiating potentially for these bispecifics if you allow bridging and Kite again does not?
For the CAR T-cells?
Yeah.
Real world, they use bridging therapy. We would want to replicate those standard of care practice as much as possible. We're allowing bridging therapy. The other thing we know is that bridging therapy is often used with patients that are progressing rapidly, right? That may disadvantage them and not make their data set as translatable to real world. We feel like we're in a good position. The other thing I might say while we're on this topic is that we're very happy with our fast-to-market approach in the third or later line because we think there are more patients who have had 2 regimens of chemotherapy prior to CAR. Patients want or physicians want their patients treated second line, very often they have to be referred in to a CAR treating center.
They have to get their affairs in order, get that apheresis chair, and so very often they get a second regimen of chemotherapy. We believe there are 6,000-7,000 patients that are available in the third or later line. We think this is a substantial market, and being first is gonna be a real advantage for us.
Are you allowing prior CAR T in that study?
We're not evaluating CAR-experienced patients because the much bigger market, the better place for Lyell to invest our development dollars is in the CAR-naive population. We intend to displace the standard of care CD19 CARs, not go after them.
I think one difference in the clinicals on the safety side, I think ronde-cel, you started in the whole cohort of pretty high ICANS, 12%. You implemented prophylaxis, and you brought that down, I think, to 4%, grade three. That's still looking a little bit higher than some of the competitors. Can you just help us understand that? Is that a comparison? With that rate of ICANS, is that gonna just always limit you a little bit to be able to go to more community centers?
First and foremost, ronde-cel has never had any grade three or higher cytokine release syndrome. When you think about the two key side effects for CAR T-cell therapy, there's cytokine release syndrome. We've had no grade three or higher CRS, then there's this neurotoxicity of ICANS. By far and away, the highest rates of ICANS observed are with the approved YESCARTA. When you talk about the data that we've shown, we now, with dexamethasone prophylaxis, have seen less than 5%. We have treated patients and are treating patients in the outpatient setting. We think our safety profile with no cases of grade three CRS, less than 5% ICANS, is exactly what patients and their physicians are looking for and gives great confidence to treat in the outpatient setting.
If anything, this is gonna expand the ability to get our CAR T-cell therapy into the community centers. When you think about it, the whole value proposition for patients is changing, right? It used to be you had a flip of a coin, 50% chance in the third layer line of going into complete response. Now you have a 76% chance, assuming our data hold. You used to have to go in a hospital. We have to worry about CRS and ICANS. Now you're treated as an outpatient. You only have to stay around the site for about two weeks. It's a much better opportunity for patients.
Got it. We've mentioned it a couple times, but you have a really bold strategy doing the first head-to-head versus approved auto CAR T study in second-line large B-cell lymphoma. That actually aligns with Dr. Prasad's [JAMA] vision that was published in December to do these head-to-head studies. I mean, I think you've talked about what gives you confidence already that you can beat CD19 head-to-head. Can you just talk about it? Not only are you product to product, you're process to process. What gives you confidence as a small company with a more naive manufacturing that you can actually. You know, you're going up against the Kite commercial and BMS commercial processes.
Well, we're obviously very confident, otherwise we wouldn't be doing this.
Yeah.
I think first we're very confident in the biology behind our product. We're very confident in the clinical data, both the efficacy and the safety profile as we've already spoken about, and we're very confident in the manufacturing. Lyell has its own LyFE Manufacturing Center. It's a state-of-the-art facility that was designed specifically to enable commercial launch. It's fully digital. It's state-of-the-art, and we have a very semi-automated low touch process. It's highly reliable and predictable, and quite frankly, it's easier than the Breyanzi process for sure. We have a greater than 95% success rate, a median vein to site time of 16 days. It is really a state-of-the-art process. We're highly confident in it. Some people think the CD62L enrichment might add time, it might add complexity, but it really doesn't. It's very simple.
We have never had a failure due to the CD62L enrichment, and again, the whole process works quite smoothly.
How does it work in terms of reimbursement? Cause I think you're having payers in the U.S. pay for the standard of care in the control arm, and then you're paying for patients on the active arm. How do you make sure that you're not introducing bias one way?
Well, if you think about it's really just the opposite, isn't it? This is very much exactly what happens on a patient's journey. They come into the center, they get approved, right? Because you wanna have Approval from your payers, whether it's Medicare or commercial insurance. We're doing that, and patients get randomized once their commercial or Medicare insurance has been approved. They get randomized either to ronde-cel or to YESCARTA or Breyanzi, physician's choice. It's a very real-world experience and directly relatable to what's happening to them today and their process. We think it's actually a good part of the trial design. It obviously helps us with our... manage our cost.
We're able to do this trial in the U.S. where we have really a large percentage of the highest enrolling centers, whether it be MD Anderson or Moffitt or all of Sarah Cannon Research Institute. A really nice footprint. I think it works out well. We're also able to do this in Australia and Canada.
Got it. You're gonna have a very real-world study. You allow bridging, standard of care choice, and you do the reimbursement.
There's no upper age limit. You can be primary refractory, you can be early relapsers, you can be late relapsers. We designed this trial very specifically to if you're eligible for CAR, you can be evaluated in the study. It's as real world as, and as a direct comparison as we can make it. You won't be able to say afterwards, the patients are gonna be stratified, so the risk should be spread evenly as we can across the two arms. It's a beautiful test, and we're doing it because we're very confident in the profile of our product.
How much axi-cel versus liso-cel do you expect on the control arm? Does it matter for your powering? Are you setting any caps?
It doesn't really matter for our powering because the efficacy, which is the primary endpoint of this trial, is event-free survival, is very similar. Obviously, the safety is different, so we believe that we have a better emerging safety profile than either of the two products. You know, we'll see. We don't care actually, but we think probably we'll see, as is happening in the marketplace, a little bit more Breyanzi use than YESCARTA use. We think it'll be relatively balanced.
Got it. Well, you got financing today. I was wondering how much of both of these pivotal trials, the third line and the second line head-to-head, does your current cash run rate support?
We've guided that the pivotal data from the third line study, we call it PiNACLE, will be available mid-next year. This trial is coming soon, and we'll have BLA submission next year as well. We've not guided on the head-to-head, largely because this trial's never been done before. We just started it. We said we'll be giving a progress update and more guidance around that in the second half of the year. I can tell you that the site activation is going extremely well at this point. Yes, we did just bring in an additional $50 million. That's good news.
Yeah. Maybe one more on manufacturing. I think sometimes the challenge has been specification thresholds. You say 95% in spec, but that's your clinical spec. How much of that do you think will translate to what FDA ultimately will have for your spec?
Yeah. We're, as I said, very confident in our manufacturing process. We've already presented our commercial manufacturing process to the FDA along with the analytical plan and discussed initial specifications. We feel like we're in a good place. We, as we said, are got our eyes on the prize, which is approval on the third or later line, which, the BLA submission will be coming by the end of next year. We're in a good place.
One last one sort of competitively. I think, you know, as you're bringing your product on board, we're seeing the T-cell engagers move early and earlier.
Mm-hmm.
I think we should see soon whether a CD20 T-cell engager on top of chemo works in front line. How do you think does that, you know, change the paradigm for patients and the need for CAR-T and the competitiveness of biologically a CD19, CD20 CAR-T?
Well, we're gonna have to see, won't we? I think that the ability to have a one-and-done treatment that has the opportunity for cure and patients do very well on is extremely attractive. I think as the T-cell engagers move into the front line, we'll see what the overall safety profile is and what their ultimate uptake is. I mean, there are some issues with exhaustion of T-cells and with late infections, so we're gonna have to see what the data show. You know, I think what's good for patients is good for everybody, I strongly believe that there is gonna continue to be demand for autologous CAR T-cell therapy. It's a one-and-done treatment.
Got it. In the seven minutes, I wanna go to your next program. An investor last night encouraged me to ask about it 'cause we have data this year and some people are really excited about it. You in-licensed a GCC CAR T-cell, it's for solid tumors, so maybe you could just tell us more about the construct and why you guys are excited about it.
This is a very novel program. We're super excited about it. We believe it has the potential to be transformative for the company this year. We're gonna be putting out data from this program in both the first half and the second half. This is a GCC, guanylyl cyclase C, targeted CAR T-cell therapy. It targets an antigen on colorectal cancer that is expressed in the vast majority, 95%, of colorectal cancers. You do not need a biomarker. It's on the cancer and its metastases. By the way, it's also expressed on about 60% of pancreatic cancers. It's a great solid tumor CAR. We know solid tumor CARs haven't worked well in the past, but this one is very different.
What it has is it is also coupled or partnered with CD19, and not just any CD19, but CD19 that releases cytokines in a very controlled way when it's activated. This CAR has shown remarkable benefit to metastatic colorectal cancer patients treated in China, which is where it was invented. In a single center, it's been published in JAMA Oncology. 15 patients had a 40% overall response rate and a median overall survival of 25 months in the third or later line metastatic colorectal cancer setting. In comparison, in the U.S., approved products for the third or later line have single digits, 6%, 4%, 2% overall response rates. They have median progression-free survival less than six months and median overall survival of 11 months. There's a huge need. Anything that has an overall response rate 20% or better is gonna bring great benefit.
This Chinese company moved this program on their own to the U.S. They got some premier medical centers to participate, Dana-Farber Cancer Institute, University of California San Francisco, and were able to show in a dose escalation, dose expansion trial in 12 patients in the highest dose, studied at that time, six patients, a 67% overall response rate. Really, quite remarkable results. We're very excited about this program. We think it's a great target. It's a really novel design that is showing benefit because we're able to get cell expansion and infiltration into the tumor.
I just wanna emphasize the design 'cause you went over it quickly. It has a CAR for CD19, that's to deplete normal B cells, I presume? That gives you a secondary signal to stimulate the T cells when they're in the periphery?
The goal is exactly that, to jump-start the expansion of the solid tumor, the GCC CARs. What happens is the CD19 cell expressing cells meet the B cells soon after infusion. They get activated. They release cytokines. This helps the other cells expand as well, the GCC cells. There are actually some doublet cells that have both GCC and CD19. You get nice cell expansion. Then these cells can get to the tumor and infiltrate the tumor. They continue to release cytokines in the tumor. We believe this really helps flip the tumor microenvironment to from cold to warm.
I didn't realize that. I thought they all doubly expressed it, but it's a mixture.
It's a mixture of cell types. That's right.
Oh, do you have to get that mixture, like, precisely defined in every patient?
It.
Is that gonna be a challenge?
It is done with stoichiometry at transduction.
Ah.
We have really controlled the amount of cytokine released by that, and it was sort of optimized in China, and they have this way to do experiments in patients with their investigator-initiated trials. They were able to come up with the right mixture, shall you say, and it's remarkably reliable across patients. We feel like this is something that originated in China. We were able to have confirmation that it worked well in the U.S. before we brought it in, and now we're really excited to be moving it forward. We have said that we've treated, since we brought it in at the end of last year, seven additional patients, including escalation to dose level three with no dose-limiting toxicities.
The program is moving forward, and we're looking forward to bringing out data in the first half of this year, coming soon, and additional data in the second half.
How are you conditioning it? Are you using Flu/Cy, or are you using traditional chemotherapy? Do you need to optimize that more?
It's a, it's a great question. Actually, this has a single day of lymphodepletion. Because you want some B cells remaining. Again, this was the protocol that was originally designed. It's only one day of de-lymphodepletion, which is great for patients.
That's great. Manufacturing. Have you brought it over? I know we've had challenges in CAR T, like with tech ops, getting manufacturing and having the product change in different people's hands.
Yeah. This process is made on the Prodigy. It's very automated. Again, it's being made by the company that we license it from currently. In Maryland, we're in the process of transferring it to our LyFE facility. Again, it's a very easy-to-manufacture product and is well on its way to being transferred successfully.
We have a minute and a half left, and then we have people in the audience. I'll open it up to anybody who has a question.
You hit on it a little bit, but the cash runway, if you could just speak to it, will it encompass the third line?
Yeah. We have cash runway into Q2 of 2027, so our hope will be yes, that it will.
I still have another one. with the GCC CAR, do you own? Did you license broader? Like, do you expect that you'd use this platform in the future to develop novel products against novel solid tumor targets?
Yeah. Well, we do believe this is a window into getting CARs to work in solid tumors in a larger way. We licensed specifically the GCC CAR from Innovative Cellular Therapeutics. It is a very interesting and novel way of thinking about how to get CAR T-cells to work in solid tumors.
Okay, maybe one more on ronde-cel in 16 seconds. Not to add more onto the plate, but do you have plans to start exploring it in other oncology or autoimmune indications?
We think ronde-cel has a lot of uses. I mean, could it go earlier, even into the front line, high-risk patients? Can it go into autoimmune disease? Can it go into other types of lymphoma? Yes, yes, and yes. Right now, we are focused. Our plate is very much full executing on the third or later line and getting this product approved. We want to be first. We want to be best in class, and we're gonna leave no doubt with a head-to-head PiNACLE study. The future has opportunity, but right now we have very focused on execution.
That's great. Thank you. Thank you, everybody, for your attention.