Okay. I'm Stephen Willey, one of the Senior Biotech Analysts here at Stifel, and very glad to have with us from Lyell, CEO Lynn Seely. Lynn, thanks for joining us. A lot to talk about. Any opening statements you want to make before we jump into Q&A?
Sure. I'm happy to introduce the company. First, Steve, thanks
Your mic there, yeah.
First, thanks for hosting us. For those who are not as familiar with Lyell Immunopharma, we are a clinical-stage cell therapy company developing next-generation CAR T-cell therapies for patients with hematologic malignancies or solid tumors. Our lead program is ronde-cel, which is a dual-targeting CD19/CD20 CAR T-cell therapy, which is really very meticulously designed to bring more complete responses and more durable complete responses for patients with large B-cell lymphoma. We're currently in two pivotal trials. We have a third or later line pivotal trial we call PiNACLE, and we're going to be presenting data from that trial in an oral presentation at ASH coming up here in just a few weeks. We'll have the final pivotal data from that trial mid-next year, with BLA submission next year. We're barreling forward towards approval. We're very excited about that.
In addition, we have a first-of-its-kind head-to-head trial, a randomized controlled trial in second-line large B-cell lymphoma, where patients are being randomized either to ronde-cel or to investigator's choice of the two approved CD19 CAR T-cell therapies, YESCARTA or BREYANZI. We will be presenting new data from a second-line cohort, not this randomized controlled trial, but a second-line cohort from our phase I/II study at ASH as well. A lot going on. Excited to talk to you about it.
All right. That is great. I definitely want to spend probably most of the time here on ronde-cel, just given the ASH data. But maybe before we dig into that, you talked about the ability of ronde-cel to expand the breadth and depth of responses that you are seeing. Can you just talk a little bit about how ronde-cel is differentiated from standard of care CD19 CAR T, and how you are achieving that breadth and depth of response from an engineering design and then also manufacturing perspective?
Sure. Design, of course, is very important, as is manufacturing. So ronde-cel is a single tandem CAR that expresses binding sites for both CD19 or CD20, so it is full potency at CD19 or CD20. This is really important because some malignant B cells are low or no CD19, so you can imagine they will not respond to CD19 CARs, where with both either/or antigen, you can really drive more complete responses. With two antigens, it becomes much harder for malignant cells to escape this antigen, or the CAR T-cell therapy, so we get more persistence. But that is not all. This program was really designed to manufacture cells in a very specific way. The field has really aligned around the fact that naive T cells in the cell product really drive better outcomes.
So our product is very specifically manufactured to enrich the high majority of cells in our final cell product to be naive or central memory T cells. We do this by a very simple process during manufacturing of CD62L enrichment. We are the only company that is doing that, and we find that is a very controlled way to get the naive T cells during manufacturing. So we think this is really, both of these things coming together, the dual targeting and the CD62L selection for naive cells, is sort of the secret sauce of ronde-cel.
I would be remiss to say that we also at Lyell invested in our own manufacturing center many years ago, and so all of our product is manufactured there. We are running our commercial manufacturing process as we speak, and we can make more than 3,000 cell doses, so get well into launch. I think this idea of a very rationally designed cell product and then a very carefully manufactured next-generation product is really important for us.
One of the two ASH abstracts that were published, updated results from the registrational phase I/II PiNACLE trial. I think we are expecting top-line data middle part of next year.
That is correct.
This is third line plus large B-cell lymphoma. Historical efficacy benchmarks are very well established. Can you just highlight how the updated ronde-cel data appears to now be tracking relative to those benchmarks?
Sure. The two leading approved CD19 CARs are YESCARTA and BREYANZI. Both were first approved in the third or later line setting with single-arm trials, very similar to what we're doing. There, the data are quite similar to one another. Overall response rates for YESCARTA and BREYANZI are 72%, 73%. Complete response rates for YESCARTA and BREYANZI are 51%, 54%, and the median progression-free survival is six to seven months. That's sort of the standard of care.
We're presenting data in the third or later line from our pivotal trial that is showing we have a 91% overall response rate, a 77% complete response rate, and I think what we're really pleased about is a median progression-free survival that is not reached. Last year, it was 18 months, and this year, it's now not reached and expected to be at least 24 months. Really continuing to improve as the data mature.
Yeah. I thought your ability to replicate that 70%+ CR rate across a larger denominator of patients was important just for establishing confidence, I think, for investors. To your point, the durability here looks to be really interesting, right? I think there was a 12-month progression landmark in the abstract that was 63%, right? Again, the benchmark here is six or seven months in terms of median.
Yeah. Our median, or our PFS rate at six months is 75%, whereas the progression rate for the CD19s, the median is six months, so 50%. So we are at 75%, they are at 50%. I think this durability, which really is ronde-cel's superpower, I think, is especially seen in the duration of complete responses. So we talked about 77%, almost 80% of patients are going into remission, but what is important is the duration of that complete response. So we are seeing at six months, 92% of patients remain in complete response. Then, of course, at 12 months, it is 75%. So this is a very high percentage.
Yeah. Durability is the gold standard for how all these therapies are judged. I know you are evaluating complete response rates at day 84. Can you say anything about how much additional efficacy evaluable patients, and maybe even duration of follow-up, that we will expect to see in the ASH presentation itself?
Yeah. So this is the third or later line. It is a pivotal trial, so we are continuing to enroll. The trial will enroll around 100 patients. We have in the abstract 44 efficacy evaluable patients. We will expect to have a majority of the patients, let us think around 60 or so patients, at least in the presentation. The data are, again, it is not just more patients, it is longer duration of follow-up, which I think, again, will continue to show what ronde-cel can do.
Okay. I believe this registrational data set excluded high-grade B-cell lymphoma patients. I know these are harder to treat. You were concerned about this trial kind of being a catchment basin, right, for those difficult-to-treat patients. But what is the typical representation of these high-grade patients within the third line plus setting, and would you expect to see this exclusion of these patients emerge on a product label?
Yeah. High-grade B-cell lymphoma in the general population is maybe 5%-8%.
Okay.
In a CAR T-cell treated population, it is a little bit higher. We have about 10% of our patients that were treated with ronde-cel had high-grade B-cell lymphoma. What we saw was we were getting a high percentage in the early days, and so we limited recruitment and have just been enrolling patients without high-grade B-cell lymphoma in the third or later line. That being said, you will see in the second line cohort, we have a lot of high-grade B-cell lymphoma patients who are doing very well. We are also continuing to enroll high-grade B-cell lymphoma patients in our randomized control trial, because absolutely we believe this product works very well in high-grade B-cell lymphoma patients.
I think the issue is, in the absence of a control arm, if you enrolled a predominance of those patients, it can sway the results a little bit. We wanted to ensure that we did not have an overabundance.
I know we have seen lower rates of grade three neurotoxicity become a really important driver of BREYANZI adoption. At least relative to YESCARTA. It appears like you're looking better on that front as well. I know you instituted a dex prophylaxis at some point after this trial had been started. I think the abstract suggests that you're at about 9% grade three ICANS right now. Is that a blended statistic that shows both those patients who weren't receiving prophylactic dex and those that were? I guess for those patients that are still getting prophylaxed, is that grade three rate kind of still in that low single digit?
It's a lot of questions in there, but I would say first and foremost, when you think about a product, efficacy drives uptake. We know that physicians are very willing to switch based upon the product profile. They're not loyal to brand, they're loyal to data. These are very data-driven physicians. So efficacy is critical, but safety is also critical because as you said, physicians want to be able to prescribe this, and patients want to be administered this product in the outpatient setting. One of the key side effects of CAR T-cell therapy is ICANS or this neurotoxicity. Yes, we're very fortunate. Our goal is to be comparable or better than BREYANZI, which is felt to be out in the field a very well-tolerated product.
On average, they have an ICANS rate around 10%, and as you saw in our abstract, our blended data is 9% ICANS, and that does include patients who received dexamethasone prophylaxis as well as those who did not.
Okay. You mentioned the second abstract that is in the second-line setting, which is where you are doing the registrational head-to-head trial now. Can you highlight just maybe what we learned from this updated look of data within the abstract, and again, maybe try to compare that to the second-line efficacy benchmarks that we know exist for standard of care CD19, which is the control arm in the phase III that you are running?
Yeah. This is, I think, a really important update for us, and I think can help give a lot of confidence in this head-to-head trial. We basically doubled the number of patients. Last year, we had about 18 patients. This year, we are seeing near the full cohort. This is not data from the pivotal trial. This is, we had a second-line cohort in this multi-cohort phase I/II trial that has enrolled 43 patients total. We have since discontinued it as our head-to-head trial has taken over, but we are going to be presenting updated data, and what we showed is a 95% overall response rate. And a 76% complete response rate, median progression-free survival not reached. And what is so important about this data set is 84% of those patients have primary refractory disease.
That means they are the sickest, most high-risk patients because they did not even respond to their first-line chemotherapy. And so that is a really good sign that this product is working and working well, even in the sickest patients, and with this kind of high response rates, and also duration of response. It turns out it is really hard to find comparable data for the CD19s. One of the reasons we think we got so many primary refractory patients in our trial is because we were enrolling when commercial CD19s were available, and so the physicians tended to put patients that they knew did not do well on CD19 CARs, is our impression. When you look at the data in the literature, the randomized controlled trials in the second line did not publish their second-line subgroup analysis.
There is one pivotal trial PILOT, which is a single-arm trial for BREYANZI in the second line, where they enrolled older patients, transplant-ineligible patients, and there they reported their primary refractory subgroup. The complete response rate was 42%. We have 76%. So, I think we are in a really good position there, and these data really help support, again, those head-to-head trials. When you think about between the combined third-line data and the second-line data, they are just in the abstracts, that is more than 80 patients, all of which are saying the same thing.
Yeah. I think it's a good point, right? Because I think when you look at the registrational studies for the standard of care CD19s that are your control arm, there's a lot of nuanced differences, right? Even the way that they define their primary endpoints and this definition of primary refractory disease is different between the two studies. I guess when you look at the implied superiority that you're showing in the third-line plus setting, what is your level of confidence that that implied superiority you're seeing as a third-line plus agent would not be directly translatable to the second-line setting?
I mean, I think it is, of course. It's all a spectrum of disease, right? So of course it's translatable, but the second-line data, if you think about it, we have the third or later line data. We also have this very sick population of primary refractory patients. All of it says the same thing, that ronde-cel is providing much better data than we've seen previously with the CD19 CARs. I'll give you yet another example that points to why we're so confident about this head-to-head trial. Obviously, we wouldn't be doing a head-to-head trial if we weren't very confident. This was data that was recently published in Blood. It's a real-world evidence trial with liso-cel or BREYANZI. It's not a trial, it's a real-world evidence data analysis from the CIBMTR database, which is an academic consortium of centers, right?
They looked at all the patients, sort of close to 600 patients that they had treated with BREYANZI, and they did publish the primary refractory subgroup. So real-world evidence typically overestimates results because it's not as well-controlled or rigorous as what you see in a clinical trial. But even that, their median or their progression-free survival rate at 12 months in the primary refractory subgroup, which is large, was 38%. Ours is 55% in our primary refractory patients. It's not close. So we're looking at really big differences, and we're at 75% at six months, they're at 50%.
Okay.
So we're in a much stronger position going into this. All the data, and that's what I think is so powerful about these two abstracts, is when you look at the totality of the data, they all say the same thing. That head-to-head trial, the primary endpoint is durability, event-free survival. ronde-cel's superpower is durability.
I think you had been previously guiding to an update of the head-to-head trial before the end of the year. Presumably, maybe that comes at ASH, but what should we expect to learn from that update?
I think, first and foremost, a lot of the update is just looking at more second-line data so you can really see why we're so confident in this. In addition, we're going to be giving some idea of the momentum in the trial, the number of activated sites, how enrollment is going. We probably aren't going to give specific numbers, but qualitatively how it was going. One thing I'd just like to sort of point out that a lot of people don't realize, this head-to-head trial is extremely strategic for us, not just so that we capture the second-line market, but we have 60 centers that are going to be activated, majority in the U.S., selected for their commercial capability.
The majority are already up and going and enrolling patients in this randomized controlled trial that is, by the way, not blinded to product. We have physician champions at these major centers randomizing to ronde-cel or to the currently available CD19 CARs. We have our teams in these centers, and this gives us a real leg up. When we get approved in the third or later line, they're going to know ronde-cel because they're using it in their centers now. I think that gives us a real leg up in this third-line launch.
I think that's a kind of really interesting point, because I know that there's been this analysis that was published out of Sloan Kettering, I believe it was.
Yes.
Maybe also supported by some additional claims data. It suggested that there is a lot of patients who are, I guess, quote-unquote, "second line," but are receiving holding therapy in between kind of frontline disease progression and eventually receiving their CAR. Maybe explain a little bit how you think that could make this third-line plus label that you are initially going to receive maybe a little bit larger than what it could be in actuality.
We actually think it is a lot larger. Most people think, "Oh, the third line is sort of small, and then when you get your head-to-head label, it is going to take off." We do not think that at all, because what we know from both this retrospective analysis from Memorial Sloan Kettering, but also our own claims analysis, Medicare fee-for-service claims analysis database work that we did, that today, one out of every two patients, 50% of patients who are getting cells collected for CAR T-cell therapy have had two prior regimens of chemotherapy, and therefore would be on label for a third-line product.
Today, nobody counts because CAR Ts are approved in both the second and third line, and if you ask doctors, they will say, "I treat in the second line." But if you rigorously count how many regimens of chemotherapy those patients have had, 50% have already had two. We think this is a real advantage for us. That fact, coupled by this idea that all of these major centers are going to be using ronde-cel in this head-to-head trial before we even get there with the third-line launch, is really, I think, going to help this launch gain steam.
Okay. We know, I guess, BREYANZI and YESCARTA collectively did about $3 billion in sales last year. That is against the backdrop of CAR T utilization rates in the U.S. still being pretty low, right? They are only about 20%. Where do you see that utilization number trending to over the next, say, like 5-10 years, and what needs to happen to move that rate higher?
Well, I think when we think about our commercial launch, there are a few things to consider. First, the number one goal is to switch out the CD19s, right? That is easy. These physicians are very data-driven. We have better efficacy data and at least comparable safety data to liso-cel, better than YESCARTA. Assuming those data hold, we would first switch out, so that is great. Remember, this is a $3 billion market today, expected to grow to $5 billion by 2030. So it is already a great market. That is before our value proposition, and I think the next way to build this marketplace is the fact that the community oncologist, this is the point you are making about a lot of patients eligible for CAR are not even referred into a CAR center. The community oncologist holds them.
Right now, you can understand it because they can say to their patient, "Well, you could stay here with me and get bispecifics, which have a 40% complete response rate. CD19 CARs have a 50%. That is close. Bispecifics have a four to five month progression-free survival. CD19s have six to seven months. So why do not you stay here with me, and I will give you bispecifics?" Think fast-forward to ronde-cel's available. Now you have a chance of 75% or 77% chance of going into remission that is now durable for a one-time treatment where you get it outpatient and you have to be at the center for two weeks. I will take that. So I think it really changes the value proposition for patients and their families, as well as the referring oncologist to make that effort.
I will point out, and we said this before, this project was designed, we never excluded patients. So we have successfully treated from day one, 75, 80, 85-year-old patients. This idea that the frail elderly cannot get CAR is just no longer true. Most patients are, in fact, eligible for CAR.
Okay. I know competition is probably something you get asked a lot about. I know Gilead just announced that they placed a partial clinical hold on its version of a CD19/CD20 CAR due to neurotoxicity concerns. I guess, knowing the structural format of that product, were you overly surprised by it?
Maybe not.
It's a bit of a leading question.
Maybe not surprised. Just for those who are not as familiar, Lyell is a CD19/20 CAR. Kite has a CD19/20 CAR that they are also developing to be next generation. Ours is a single tandem CAR that has both binders for CD19 and CD20. They're having cells express CD19, which is YESCARTA, and the CD20. They have to have two CARs, and one of them is YESCARTA, which we know suffers from neurotoxicity. They initially showed up with their first really clinical data at ICML Lugano in about 2025 with a standard manufacturing process, and they had about half, 46% of their patients were getting neurotoxicity. It was grade one, two, but half the patients, that's probably too much, right?
They then said, "That's too toxic." They came with a rapid manufacturing process, which is really geared, that's their way of getting naive T cells. We do it with CD62L selection in a controlled fashion before we infuse. They do it with this rapid manufacturing, and then the cells expand in the patient. Is this something to do with rapid manufacturing? We know BMS and Novartis are also having some issues with rapid manufacturing right now. Or is it because of the YESCARTA component? We do not know. Or maybe it is some combination of the two. But they are there right now. This again makes us sort of have this open lane, and we are sailing forward.
Okay. I think the other competitive question we get asked a lot is on the Legend side. They have an in vivo CAR T product, CD19/20. We saw data for the first time at EHA. It sounds like they are going to have some updated data at ASH. Just maybe what was your takeaway from the maybe not so incremental amount of patients that were in the abstract? I think there were like seven or something. How do you message this to investors who are somehow concerned about the longer-term existential threat of in vivo CAR T?
In vivo CAR T is a great new technology. Look, we are a next-generation CAR T-cell company. Of course, we are thinking about in vivo CAR. We have a best-in-class binder. But this has got a ways to go, and I think the Legend data really suggests that. We are in large B-cell lymphoma. There is precious little data on in vivo CAR in large B-cell lymphoma. I think we can sort of count them on one hand. When you think about what a CAR T-cell therapy has to show, you have to have acute safety, you have to have durable safety, you have to have complete response rates, and you have to have duration of response. That is four big variables.
When you think about what data do we have in large B-cell lymphoma with in vivo CAR, I mean, none of those yet are asked and answered. There is a long way to go. ronde-cel is here today, and it is going to take years for that to come to fruition. I just have to say, once we get switched in with the data that we have, we have 90% response rates. I mean, it is going to be very hard to come in with something better than that. We really think of in vivo CAR as something that can expand access to more patients when it is ready, and that is going to be years, probably.
Okay. Maybe just in the last few minutes, we can talk about the other autologous CAR that you have—
Oh.
—in phase I development.
Yeah.
This is a GCC-targeting CAR. It is in development for late-stage colorectal cancer. Maybe you can talk about how this product has been engineered to overcome what has been a historical challenge, trying to get CARs to work and work safely within the setting of solid tumors.
Sure. Lyell is very serious about developing CAR T-cell therapy for solid tumors. A couple of the key barriers have been it is just very difficult to get significant cell expansion in solid tumors, and also, there is this very hostile tumor microenvironment that very rapidly exhausts CAR T-cells. What the inventor of this product did, and we licensed this from a Chinese company, was he picked a target, guanylyl cyclase C, or GCC, which is a great target for metastatic colorectal cancer because it is highly expressed in both the cancer and the metastases, and he coupled it with CD19 CARs. Not just any CD19 CARs, CD19 CARs that are engineered to release cytokines when activated. We actually infuse a mixture of cells. Some are GCC only, some are CD19s that secrete cytokines, and some are doublets.
And so, what happens is, we put this mixture of cells in, they hit the B-cells, because there's only one day of lymphodepletion, the cells start to expand quite rapidly, and then they can infiltrate into the tumor. And these cytokines continue to be, particularly with these doublet cells, activated, so it actually helps turn the tumor microenvironment. And we came across We were very interested in this target. We came across this product when 15 patients were published from China in a single-center publication and had an overall 40% response rate. Well, 40% overall response rate in colorectal cancer is impressive. This Chinese company brought it to the U.S., got UCSF and Dana-Farber to put it into clinical trials in the U.S., and treated 12 patients and had 50% overall response rate across two doses.
This is an active CAR, and so at that point, we brought it in and are busy developing it.
Okay. I know you pushed the next data update into next year, and I think that was done to accommodate some tech transfer work that you're in the process of completing. What should we expect just from the next disclosure around that program? And I guess, how are you going to be defining success?
Yeah. So, we're doing the work of phase I, and so there are multiple things we're working on. Sort of one is, as you pointed out, we just successfully tech transferred the manufacturing process from this Chinese company to our LyFE Manufacturing Center, so that's great. It's a very automated process, but it gives us more control, particularly on the analytics and the cryopreservation, so that's great. We're studying that. We also are still working on finding the recommended phase II dose, as well as the optimal safety management plan. So, what the work of phase I is to allow this program to go straight to pivotals, right? There's not a big gap, so we want to make sure we get it right before we go to the agency and talk about next steps.
Okay. And I know that discussion with the agency, you at least previously were suggested that there might be an opportunity to expand that phase II into a potentially pivotal single-arm phase II trial. When do you expect to get regulatory feedback on the viability of that strategy?
Yeah. We've already amended the protocol to allow that. We would take the data we have to have an end-of-phase I meeting to meet with the FDA about that, but we're set up to do that quite seamlessly. It's possible that's never been done in colorectal cancer before because no product has had that sort of response rates to allow for that. It's possible another design they allow is a randomized control trial with accelerated approval based upon response rates, with the primary endpoint being overall survival. We have a couple of different options. All of them are great for us, and so we'll see what we ultimately decide to discuss and what we align with them on to do.
Okay. Maybe just lastly, what does the balance sheet look like and just kind of what that allows you to execute on going forward?
Balance sheet just got better. We closed Q3 with $194 million, and then we, at the day the abstracts were announced a private placement of $80 million. That's not included in that $194 million, and that gets us into 2028. So, through the pivotal trial data, through the metastatic colorectal cancer update, and the BLA submission for ronde-cel.
All right. No one has any questions. Lynn, thank you very much. We are looking forward to ASH.
Yeah. Thank you. Appreciate it.