Lyell Immunopharma, Inc. ($LYEL)

All right. Good afternoon, everyone. I'm Stephen Willey, one of the senior biotech analysts here at Stifel. I'm 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 a 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. But 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. And we have 2 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. And then the second, very novel CAR for metastatic colorectal cancer. So I look forward to telling you about those. / And then I should also just make note of the fact that Lyell is a little bit unique in that we have our own manufacturing like facility where we can launch from that facility and get well into launch with our own manufacturing. So that puts control under our own destiny, which we really like.

Okay. That's great. So 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 CD19/20 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?

Yes. So our CAR product, the CD19/20 construct was very rationally designed by a brilliant engineered biologist at UCLA, known as -- her name is Dr. Yvonne Chan. And this is a tandem CAR. So it's a single CAR construct that binds either CD19 or CD20 with full potency. So she meticulously did this work to ensure full potency at either. So all in just one CAR construct. So that's important because we are looking to get more complete responses and longer duration of response. And we know that some malignant B cells that cause lymphoma have low CD19, so may not respond well to CD19 therapy alone. But with the CD1920, the dual targeting, we can drive more complete responses. And then one of the key mechanisms of escape from CD19 CARs is loss of antigen. These cancer cells are very smart and they can drop one antigen. It turns out it's much more difficult for them to drop 2. So that gives you longer duration of response. And then 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 T cells and have a tendency to persist longer and have more activity and can help us with a bit more softer safety profile. So 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. So 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. And 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. But you are exactly right, Steve, when you talk about whenever you're looking at lymphoma data sets, 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 earlier late relapse from their frontline therapy. And so 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 lines, 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. Now how does that compare with the approved CD19 CARs in their label, you have -- [ Cardia ] and Breyanzi are relatively comparable. They show with in terms of efficacy, they show about a 70% overall response rate and a 50% complete response rate. So about 20 percentage points lower than we showed. But more importantly, the median progression-free survival for the approved CD19 CARs is 6 to 7 months. We have 18 months. So it's not a subtle difference. And 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. So that's the third line, which is, we think, a really important market for ronde-cel. And then 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 sort of the sickest of the sick, those patients who don't even respond to frontline chemotherapy. And there, we were able to show an 83% overall response rate and a 61% complete response rate. And so it sounds a little bit lower than the third line, but it's because it's such a sick patient population. And 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. So it's these data, particularly when you look at the 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.

Okay. So 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? And I know you've guided to a top line data disclosure, I think, in mid-'27 and the BLA submission at the end of '27. 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 kind of a snapshot of durability from the last cut?

So 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. And so 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 6 months after their complete response -- after their first response. And so 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. So this is going to be a meaningful update, and I think we'll give investors a really great look at ronde-cel. This, as you know, the data have been quite consistent. We've had our dose and 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 -- it's a popular topic for all biotech executives right now. But how would you characterize the current regulatory environment at FDA? We followed Arcellx. This was always a question we were getting from investors. Obviously, Prasad is no longer at the helm of CBER, but he was obviously a very vocal opponent of granting full approvals to CAR-T therapy on the basis of single-arm data and I think pending editorial in December that suggested that randomized OS data would be needed for full approval in earlier lines of therapy. So have you just had any post-Prasad interactions with the agency on some of these topics? And 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. But 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. So our FDA interactions to date have suggested that a full approval could be possible with this third or later line single-arm study. But 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 head-to-head randomized controlled trial, ronde-cel versus investigator's choice of Breyanzi or Yescarta. So 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. And remember, we have RMAT designation, which says that 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. So we are getting sort of the most attention there that sort of as the designations allow. So I'm very optimistic. And then 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. So we're in a very good position, we believe, from a regulatory standpoint.

Yes. So you initiated the head-to-head study you just referenced earlier this year. Again, 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. So can you just speak to that part of the...

Yes. 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 the 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 relapses. So 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. And even today, you may be aware that Kite Gilead is going to run a head-to-head. They also have a different CD1920 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 that program for well over a year. And they are not taking -- 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. So a little bit more real world, and we think that's going to be very much to our advantage.

Yes. And 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? And I know in your opening statement, you referenced a tandem binder that was engineered in the 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 2 products in this setting?

I mean I think the data are going to speak for themselves as time goes by. I think so I have to speak in theoreticals. But I think what typically is thought of is that a tandem CAR means there's CAR expressed. So that's advantageous to the cell. If you have 2 CARs expressed, it's more metabolically difficult for the CAR to express. And in this case, one of the -- in the case of Kite, they're expressing Yescarta for the CD19 component and then a CD20, a separate CAR. So 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. And then there's some school of thought that having these 2 different CARs, one with a CD28 co-stimulatory domain may lead to sort of more T cell exhaustion, which would not be good for durability. So these are theoretics. We're going to have to see how the data play out. But 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 kind of 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. So 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. And then they pulled out altogether. And 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. And over time, we knew that J&J was going to these same sites and saying, oh, we want to run a study, and they were told, no, well, we've already committed to Lyell, and we're working with Lyell in the study, which is what -- so we turned them down. And so 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. And so 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. And so I think we took a very aggressive strategy, and I think it paid off. But for whatever reason, it doesn't matter, this is great news for Lyell because it's one less significant competitor in the marketplace, and we think sets us we're clearly in the lead at this point and not by a small margin. So to be honest, it's 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 is trying to do with their ALPHA3 trial, where they're looking at cema-cel as consolidation therapy 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 mean I'm always happy when cell therapy companies do well like Arcellx being acquired because all boats flowed. But I think in terms of threatening ronde-cel, no. I think this is an allogeneic product. They are going into -- 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, right? We didn't get any durability data. It wasn't the primary endpoint of the story of the study. So they've got a ways to go. And it's -- for us, it's a small patient population, right? I mean it's not going to take away the major percent of the population because when you sort of look at even if there are 20% or 25% of patients are MRD positive after frontline therapy, half of them get testing and get cema-cel. It's a pretty -- it's not a major drawback for us. So 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.

Okay.

So I know -- so Legend just announced that they're going to be presenting some preliminary data for an 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. But 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?

So I -- 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, right? We've worked hard to get this next-generation CAR T cell therapy. So we are very excited about in vivo and interested in it as well. But -- if I were going to say this is threaten ronde-cel, I would say, no, I think it's complementary because the probability, I mean, Legend is 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 duration -- median progression-free survival of 18 months. They just dosed their first patient in the summer, right? So 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. So 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. And so I think where I sort of see in vivo being very important, autologous CAR is the gold standard, right? And these -- our CD19/20, I think, is putting up data best-in-class. And so we believe we're going to be able to improve access because the value proposition for patients and for providers is improving. And then in vivo CAR can expand that access. That's a great thing for patients and the field at large. But do I think in vivo first shot out of the first time up bad is going to replace and threaten autologous CAR, Maybe, but I'd be surprised.

Okay. Maybe in the last few minutes, we can switch gears to 273. So this is the GCC targeting CAR that you in-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 GCC that's expressed on tumor cells. What does that buy you from a biological perspective?

Yes. So 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 GCC is a great target for metastatic colorectal cancer because it's upregulated in more than 95% of them. But we know a target alone is not sufficient. And the inventor of this CAR realized that there were 2 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. And so the concept is there's GCC CAR expressed. This is a dual targeting product and separate, this is a CD19 CAR expressed. And here, what you have is the CD19 CAR is engineered to release cytokines or supportive hormones, you can think of it as. And so CD19, you're going, wow, that's a B cell target. Yes, 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 jump-start cell expansion. And in particular, we get nice expansion of these, what we call doublet cells, which have both CD19 and GCC, which can get into the tumor with secretion of cytokines and warm up that tumor microenvironment. And then the largest number of cells are GCC alone, they get in and kill the tumor. And so we've been seeing response rates across 2 dose levels in the 50% range. So 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. And we 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?

So we're in the first half coming soon, we're going to have an update on the program. And 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. And the patient actually died from an infection. The colitis was controlled that 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. So after this case, a significant prophylactic regimen was put in place with a safety management plan. And so 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. And then 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 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 transferring that in? And then what are your options to scale capacity for each of these products?

That's a great question. So 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 GCC CAR program. It's very automated. So it's sort of made on the Miltenyrotiggy, and it's quite easy and standard to run. So 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. And I think we can do both within our facility.

Okay. And then 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?

So 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.

Right. Well, we're out of time, Lynn. I really appreciate it. That was great. And thanks, everyone, for listening.

All right. Thank you.