Great. Thank you, everyone. My name is Max Skor. I'm a biotech analyst with Morgan Stanley. Before we get started, I have to read these quick disclosures. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. I'm happy to share that we have Lyell Immunopharma here today. Just to begin with, for those in the audience who may not be familiar with the Lyell story, could you give us a quick background and any high-level takeaways that we should keep in mind?
Sure. I'm Lynn Seeley. I'm the CEO of Lyell. Lyell Immunopharma is a clinical-stage oncology company focused on bringing next-generation CAR T cell therapy to patients with cancer, both hematologic malignancies as well as solid tumors. We take the patient's own living cells, their immune cells, very specifically their T cells, send them to our manufacturing center where we engineer and expand them into very personalized, potent cancer-killing cells. We then send them back to the patient. We're currently in pivotal clinical trials with our lead program, which is known as RONDACELL. It's a dual-targeting CD19, CD20 CAR T cell therapy for patients with aggressive relapse refractory large B-cell lymphoma. We have a single-arm pivotal trial in the third-line setting underway and are in the process of initiating a second-line randomized controlled trial.
Great. Thank you. Before we dive into the lead program, what kind of gives Lyell Immunopharma its edge? Why do you think, why do you believe the platform could win in large B-cell lymphoma and eventually in solid tumors?
Sure. Lyell Immunopharma was set up very specifically to bring next-generation cell therapies to patients. We have a phenomenal research team. Our Chief Scientific Officer has been working on CAR T cell therapy for decades. We have an amazing clinical development team that has very specifically been built for cell therapy. Our Chief Medical Officer has been doing cell therapy for decades. We've already invested in our own manufacturing center. We're set to do cell therapy. We have this lead asset known as RONDACELL, which targets both CD19 and CD20 with full potency. It's known as a true or logic-gated CAR. This gives it several advantages. First, it can target malignant B cells that might have low CD19 antigen expression, as well as those with CD20. It gives you two chances to really have potent cell killing, which we believe can result in more, deeper complete responses.
In addition, when there are two targets, the malignant B cells are much less able to escape. Antigen escape is a known mechanism of resistance for the CD19 CAR T cells. We believe ours will be less likely to have antigen escape. Finally, we select our CAR T cells to be naïve. We have a CD62L selection in our manufacturing process. We're the only company that does this, and it gives us a very high percentage of naïve T cells in our final product. Overall, we believe our product is well positioned to have more complete responses and better durability of response, which is really what patients are looking for, right? These long treatment-free periods when they're disease-free.
Great. Thank you. Now diving into RONDACELL and the lead program. Last week, I believe you just announced the design of your phase three trial. Maybe if you can give us a high-level overview of that, and then we can dive into some details there.
Sure. We already have ongoing a single-arm pivotal trial in the third-line setting for large B-cell lymphoma. We wanted to work to get it approved also in the second line. For a second line in large B-cell lymphoma, a randomized controlled trial is required. The standard of care by the regulators is really still chemoimmunotherapy. At CAR T cell centers, they believe equipoise is broken, that CAR T cell therapy is the treatment of choice for patients in the second-line setting. We are running a head-to-head trial against investigators' choice of either axicabtagene ciloleucel or Breyanzi because we want to leave no doubt. We want to provide physicians and patients with the best information to show that our CD19, CD20 dual-targeting CAR is better, superior to the CD19 CARs that are out there.
This is a very carefully designed trial to achieve the data that patients and physicians will be looking for.
This is the pivotal trial, correct?
This is known as Pinnacle head-to-head. We have two trials we're calling Pinnacle as our single-arm third-line trial, and Pinnacle head-to-head is the second-line head-to-head study.
OK, can you walk us through the primary endpoint, enrollment expectations, any details there?
It is obviously early days, but we have very aggressively been recruiting centers for a while now. We have announced a very renowned steering committee to really show the extent of the preeminent lymphoma and cell therapy experts who are working with us. We intend to enroll 200 patients per arm. It is a very well-designed, well-powered study. Predominantly, this will be in the U.S. We will also have some sites in Australia. The primary endpoint is event-free survival. This is very consistent with the primary endpoint of other trials in the second-line setting.
Can you walk us through just level-set expectations going into the readout, timing of enrollment, and as you noted, the primary endpoint? What can we expect?
It's early days. As I said, we're not giving details right now on the timing in the second-line study because we want to get some time to get the sites up and going and to see what recruitment will be like. We have said we will begin enrolling patients by early 2026. For those who know the field, it can take months to get these sites up and going. We've been working on this for quite some time, so we're well on our way and we'll be providing updates. With the endpoint of event-free survival, we have an opportunity potentially to do an interim analysis. You may be aware that Breyanzi did an interim analysis in their trial and got out a little bit early. We'll see how things shape up over time.
In the meantime, we have what I call a fast-to-approval strategy with the third line, which is a single-arm pivotal trial.
Great. You also announced the formation of a steering committee. Why is their involvement important for credibility or execution? Yeah.
Whenever you're running a large randomized controlled pivotal trial, particularly one that is precedent-setting, a head-to-head CAR T cell trial, you need the very best trial design. You also want the very best centers participating with you. I think it's a statement to Lyell Immunopharma and the credibility of our RONDACELL data that some of the very best in the field have chosen to be on our steering committee: MD Anderson, Moffitt Cancer Center, some of the very big leaders in the field. What they're doing is they've helped us design the trial, so it is very broad in its inclusion criteria. We wanted it to be very favorable to patients and physicians. If a patient is eligible for CAR T cell therapy, there's a very good likelihood that they're going to be eligible for this trial. Physicians can use investigators' choice, either Breyanzi or Yescarta, which they like.
It gives them that flexibility. Finally, we don't have any age limit in our trial. One of the things that we've been able to show with RONDACELL is that it has a very nice safety profile that's amenable to outpatient therapy. We've successfully been able to treat patients in their 70s and 80s.
OK. Stepping back for a second, can we just talk about potentially the unmet need and key clinical signals to date?
Sure. CAR T cell therapy really has transformed the setting for treatment for large B-cell lymphoma. Previously, there was just chemoimmunotherapy, which didn't work well. With the CD19 CARs, you have about a 50% complete response rate in the third or later line. That means 50% of patients don't respond. The median progression-free survival with the CD19 CARs is only about six to seven months. There still is plenty of room for a next-generation CAR. This CAR T cell therapy that we're bringing is very rationally designed to be a dual-targeting CAR with full potency either at CD19 or CD20 to bring more complete responses and greater duration of response. For example, in the third line, we recently presented data at the big lymphoma meetings, ICML, held in Lugano in the June time frame this past year.
We were able to show an 88% overall response rate and a 72% complete response rate, markedly better than what has been seen with the CD19 CARs. It's quite a thick patient population. We also presented what I call a sneak peek, an early look at our second-line data, again in an older patient population with a substantial amount. Basically, 82% of patients had primary refractory disease and were able to show a very favorable overall response and complete response rate.
Great. Before moving into maybe a discussion around market positioning and differentiation, what additional data should we expect by year-end, particularly in the second-line setting? How could that influence timeline?
Charlie, maybe I'll let you jump in here.
Yeah, yeah. We will have more data later this year, both in the second-line setting, importantly, which will obviously guide us into the initiation of the pivotal study to begin next year, but also additional data following up on the third-line setting as that has continued to enroll into the pivotal study. We'll be updating on both later this year.
OK. Is there any guidance you want to put out on maybe digging deeper and what expectations are going into the additional data into the year-end?
We haven't provided more guidance with granularity on a number of patients. You did ask about timelines earlier. While we haven't given guidance on timelines for the second-line study, we have given guidance on the third line, and we anticipate a BLA filing in 2027. You can kind of think through, obviously, what you need to be able to get there from here. It's already late 2025, so that feels like right around the corner for them.
Could you lay out maybe some more details in regards to the next steps or gating factors to BLA submission?
Maybe I'll take that. I think always the first thing is we have to complete enrollment. We've said that we are increasing the number of sites when this is a really beautiful trial design. It was set up as a phase one, two trial that could seamlessly expand into a pivotal trial. The patients that we've already presented are part of this pivotal trial, and we're continuing to enroll it. We've made an effort now that we're in the pivotal trial to increase the number of centers. We'll be seeing more centers come on as they're already coming on, and more will be coming by the end of the year. That really will help us set the recruitment rate. We will follow the patients in addition to the primary endpoint, which is overall response rate.
The agency also looks at duration of response, and we'll follow all patients for six months after their first response.
Great. Very helpful. Now moving into market positioning, how do you see switching behavior playing out in the CD19 CAR T market today? What's Yescarta's current share?
Yeah. If you look at the switching that's occurred in the CD19 space to date, and I think we've seen a similar dynamic in the BCMA space, you do see a high level of switching as you either have products that come along with improved safety profiles, in the case of Yescarta and Breyanzi, or in the BCMA space where Carvykti obviously came along with better efficacy. When a better product comes along, you've seen rapid, significant switching occur. What we've seen as far as market share, I think that Breyanzi is still trailing Yescarta a little bit at this point based on the public data that we've been able to look at. It looks like Yescarta is about low 50s, 52% or so of the market, and Breyanzi is slightly behind them. It's expected to overtake them over the course of the next couple of years.
When we see that dynamic with this kind of rapid switching that's occurred both in the CD19 space and BCMA space, you alluded earlier to the unmet need. We don't even necessarily think of it as the unmet need of patients that aren't being effectively treated with CD19s today, but the need as a whole and being able to replace the existing therapies and going toe to toe, which is a large part of the reason why we're doing a head-to-head study. As we think about that need, about 30,000 patients or so in the U.S. with DLBCL, about 12,000 of those progress to the second line and beyond. That's really the market that we see within the U.S. As you probably know from Yescarta and Breyanzi, there's a significant opportunity outside the U.S. as well. About half of their sales come from outside the United States as well.
We're not going after the Breyanzi or Yescarta failures; we're looking to really beat them in that second-line patient, 12,000 patient population in the U.S.
To underscore how important this market really is, it is unusual in that it is so data-driven and so quick to change, first with better efficacy, but also with safety. By providing this head-to-head data, it will give us this very strong ability to completely disrupt this marketplace. There has been tremendous enthusiasm from investigators. I think we're very pleased with the evolving footprint that we have. This will, of course, be our commercial launch footprint in both major academic medical centers as well as in the community. I think the enthusiasm for the sort of data that we're going to be able to generate, combined with this switching marketplace, puts us in a really wonderful position.
You've already kind of alluded to it earlier. What key biologic or clinical features make RONDACELL disruptive compared to CD19-only therapies today?
Yeah. I think, again, it really comes down to three things. We get, we believe, more complete responses because we target both CD19 and CD20. You can imagine more killing of B cells because some have low CD19 expression, and then we can hit them with CD20, where a CD19 CAR can't. Less antigen escape because it's much harder for malignant B cells to drop two antigens than it is one antigen. We're the only company that does CD62L selection, which is a very short four-hour process in our manufacturing that allows our final product to be a very high percentage, 90% or more, naïve CAR T cells. We know naïve CAR T cells are more likely to expand and persist over time.
We think this gives us this very rationally designed CAR to bring more complete responses and longer duration of response and puts us in a very good place to disrupt the CD19 marketplace.
OK. I think that's a great place to start and move into potentially safety. Can you expand on your mitigation strategies for ICANS or CRS and how they compare to existing therapies today?
Sure. So whenever you're developing a CAR T cell therapy, you need to contend with some of the side effects which can develop. CRS, or cytokine release syndrome, and ICANS, which is a neurotoxicity adverse event. I can say we're very pleased with the safety profile of RONDACELL to date, potentially because we have more naïve T cells. They are a little quieter coming out of the gate. We believe that's what allows us to treat older patients, for example, quite easily. It's why we're allowed to treat them in the outpatient setting. What we've seen is that we have a CRS and an ICANS rate that's better than maybe Yescarta, but in line with Breyanzi.
That's before we instituted some low-dose dexamethasone, which is three days at the very beginning around infusion of 10 milligrams of dexamethasone, which has been shown to decrease some of these toxicities that we've been discussing. We've had good results with that to date. We're very pleased with the safety profile of the product.
When you speak to KOLs or prescribing physicians, is there anything that they highlight in regards to the safety profile?
Yeah. I think they've been very pleased with it. I think we are using as the co-stimulatory domain a 4-1BB CAR. 4-1BB CARs, which is different than Yescarta, for example, which is a CD28 co-stim domain, have less side effects, neurotoxicity in particular. I think what has been so impressive to the experts and why so many people are joining our trial and have signed on to our steering committee is because of this combination of really what appears to be better complete response rates than have been seen with the CD19 CARs, as well as a safety profile, which is very much in line with Breyanzi, which is felt to be the safest CAR out there today.
OK, moving on to manufacturing, because I think that's an important part of your story, what is your facility able to scale to at this point? What are the commercial readiness timelines going forward?
Yeah. Our facility up in Bothell, Washington has been built out as we've been able to manufacture all of our CAR T product here for the last few years, actually. We built it a few years ago, and it provides us the ability to really scale up not only through the development of the products, but also importantly into commercial launch. Out of that facility, we can do about 1,200 doses per year, which is a big % of the overall CAR T market today, which gives us, I think, plenty of flexibility to be able to do an early commercial launch out of that facility and be able to think about strategies as we get closer to commercialization around expanding manufacturing to additional facilities, CDMOs, potential strategic collaborations as well that can help broaden out that.
We feel very good about the capacity that we have today, and it's really just a function of headcount and how many people that we need to hire, manufacturing individuals to be able to manufacture the product at the facility as opposed to any additional capital expenditures that need to be made.
OK. Can you just elaborate a bit on what's your go-to-market plan and prescriber education strategy?
Yeah. The very best go-to-market plan is, of course, to bring very strong data because this is a very data-driven group of prescribers. That's why you see this dual strategy of a very nice third-line study as well as the randomized controlled trial in the second line. We have worked very hard, as I sort of alluded to, to have a very strong group of clinical trial sites in our pivotal trials. This gives us a great advantage in terms of commercial launch readiness because the major centers, both academic as well as community centers that have clinical trial expertise, will already have experience with our drug. We will very carefully and intentionally build our commercial team. This is a great area for a smaller company to be able to manage because the centers are relatively few in number. It's a very targeted sort of sale, very data-driven sale.
We'll be leaning in a lot to medical affairs as well as peer-to-peer education. We're very pleased with our ability to be ready. As Charlie just alluded to, a very critical success factor is that we hold control over manufacturing. We can launch from our current center. You can't underestimate what an advantage that is. With a very stable workforce, one of the hardest things of working with CDMOs is the turnover of staff and employees and retraining. We have a very dedicated, stable, wonderful experienced team at our manufacturing center.
OK. Can you also touch on just the competitive landscape? How do you view remaining CD19, CD20 competitors, especially J&J? Where does Lyell have the edge?
Yeah. You want to start with that, Charlie?
Sure. Yeah. Look, I think that our biggest advantage, if you look at the other CD19, 20s, it's really J&J and Gilead that have the two other competing products out there. Our product and J&J's are very similar to one another. Gilead's is slightly different in that they have two CARs as opposed to our tandem CAR structure. I think our biggest, highest level of confidence is around not only demonstrating more improved efficacy relative to the CD19, but also being very much in line with our peer CD19, 20s. What we've seen through some of the earlier data is that our approach and J&J's as well, given it's a very similar product to ours, has a better improved safety profile relative to Gilead, which we think is going to continue to have the Yescarta-like safety, liability, and toxicity concerns.
We feel very good about our position and think that given our position, with what we believe to be a best-in-class product, but importantly with the leadership position from a timing standpoint, already starting the pivotal study in the third-line setting here in the U.S. and importantly kicking off that second-line head-to-head study, we can really separate from the pack and have not only best-in-class, but potentially first-in-class as well.
Maybe just to add to that, I think what has really been transforming in the field, even just in the last six months, was when you came through the spring meetings, which are sort of ASCO or the European Hematologic Associated Meetings, and then culminating with Lugano or the International Conference on Malignant Lymphoma. They had a session where everybody who was sort of developing a CD19, CD20 CAR presented one after another after another. What became clear to the experts in the field is, wow, CD19, CD20s are coming because each company, Gilead, J&J, and Lyell Immunopharma, put up better clinical outcomes than had been seen with a CD19. It's no longer just, you know, one, maybe are these data better?
It was three companies with different CD19, CD20 products all putting up data to say, this data looks like it's going to be next generation and replace the CD19. It becomes a question of, who's in the best position? I think as Charlie alluded to, we believe we are for a couple of reasons. We do have dominant intellectual property position. We also have started our program. We have selected our recommended safety dose before the others. We have an ongoing pivotal trial in the third line. They're sort of the first to announce this groundbreaking head-to-head trial. We are being bold. We're being aggressive. We are working with some of the best centers and experts in the field. We're very pleased with our position. We're very pleased with our product. What's really important is we are able to treat a broad range of patients.
If you go back and you look how Yescarta and Breyanzi were developed, and particularly Yescarta, they focused on a relatively narrow range of patients. They had age limits. They only allowed certain patients. We are allowing a much broader range of patients, taking sick patients, a lot of primary refractory patients, and still seeing better data. We've been very transparent in the sickness of our patients, if you will, both in the second and third line and putting those data out there. I think that speaks a lot to the investigators. You're asking what makes some of these experts excited? Yes, the overall efficacy and the safety. In particular, we're seeing benefit in second-line patients with primary refractory disease. That is really distinguishing, according to the experts. We're pleased with our position. It's going to be a race as always.
We think those who put up the best data the soonest, they're going to be in the best position.
Are you keeping an eye out from Gilead and J&J, any updates in the near term that you're watching or we should keep in mind?
I think we have obviously yet to hear about their strategy. I think we're being quite transparent and bold in our strategy. I think the end of the year is typically a time when people update the data. I think we're watching the safety profile of Gilead's product. As Charlie alluded to, it's a bispecific or two CARs. Their CD19 is actually Yescarta, which has some safety liability. If you look at their overall rate of ICANS and if you look across overall ICANS between J&J, Lyell, and Gilead, Lyell has the lowest and Gilead has the highest. We're going to see how that plays out over time.
Would you like to touch on your IP strategy?
I think we have an IP of what we believe to be the dominant IP position that dates back to 2014. We think that's important. I think J&J licensed their product from Able Data, which is a company in China. It has, as we said, a highly similar structure to RONDACELL.
Great. Maybe moving on, talking a little bit about the pipeline. What's your timeline and design strategy for your solid tumor program?
This is near and dear to our hearts. We continue to love our hematologic malignancy program, obviously. The holy grail in CAR T cell therapy is for solid tumors. The solid tumor field has been evolving quite a bit, as first-generation CARs had a single activation domain in the CD3 beta. Then we added next-generation CARs where they had a co-stimulatory domain. Now we realize we need that plus two more signals. I think this has come from our own work where we've validated some anti-exhaustion technologies, which are novel to Lyell Immunopharma, but from work of others where also you need some cytokine signaling through the JAK-STAT signaling pathway. When you bring all of these things together, we believe that is going to be what's going to allow for that really full activation of the T cell so you can get the potent and durable cell killing.
We are bringing forth a fully armed CAR, which is going to take into account each of these signaling requirements. I look forward to submitting an IND of that in 2026. We've not disclosed the target at this point for competitive reasons or exactly which technologies we'll be using. That's sort of news that will be coming in the coming months. Right now, we really want to focus people on our hematologic malignancy program because we think, as Charlie said, we're leading the way there with a really excellent product.
Great. Exciting 6 to 12 months ahead, definitely on the clinical side. Maybe we can touch on just the financials. You could walk us through, I believe you had a private placement recently, $347 million pro forma cash, how it's going to support the pivotal trial and the pipeline overall.
Sure. We do have $347 million cash, as you had alluded to. We've been burning historically about $35 to $40 million per quarter. That burn rate went up a little bit late last year, early part of this year, as we did the acquisition of ImpactBio. As we've completed that integration, that burn rate has come right back down to where it was prior to the acquisition. That gives us cash into mid-2027, importantly, and through the pivotal data on the third-line study. It won't get us through pivotal data on the second-line study. Obviously, that'll come later. Fortunately, we've been blessed with having a significant amount of capital that has allowed us to build the company in what we view the right way.
As Lynn alluded to, having our own manufacturing facility and what that's enabled us to do to move quickly, to be able to move seamlessly from research and the development and with process science and process development to be able to manufacture the products on our own. We feel very good about our ability to push forward not only with both the pivotal studies with that capital that we have in-house, but also importantly some of the earlier stage solid tumor programs that you alluded to.
Very good. We have a couple of survey questions in regards to emerging topics. Is there anything you'd like to highlight before moving on that maybe I missed or investor-focused that you would just like to call out?
The one thing I didn't answer was the financing. Sorry, I overlooked that. We did do a recent financing. It was up to $100 million PIPE financing where we drew down $50 million at closing at a 30% premium to the then-current stock price. There is another $50 million that's a put-call structure where if we achieve certain milestones, one of several milestones over the course of the next year, we can put another $50 million to investors at a 150% premium. Investors can call at any point in time during the course of the next year another $50 million at a 200% premium to the then-current stock price at the time that we signed the transaction. Our stock was about $10 a share at the time. The first tranche was at $13. The second tranche could be either $25 or $30 per share, depending on who puts or calls.
Very good. Thank you. We'll move on to a couple of survey questions, which we're asking all of our companies. With China's rise in biotech innovation, how are you thinking about your competitive position here? Will it influence your R&D or BD strategy?
Certainly influences our BD strategy, absolutely. Obviously, we have two jobs in business development. One is to make sure that we're cultivating relationships with larger strategic potential partners as we think about commercialization longer term. As I alluded to earlier, given we've been able to be blessed with having so much cash over the course of the last several years, we haven't had to push forward with partnering too early. Our view has been, if we have the capital and investors are willing to finance the company, let's develop the therapeutics and build value on our own before we start thinking about how to share that with others unless we can really make the pie much larger as opposed to divvying up the pie. The other component on the business development side where we spend a lot of our time and effort is looking for other opportunities.
ImpactBio is a great example of that where we were looking for other products that we could bring in that could really help advance the company, move us closer to commercialization. That was really an elegant transaction, I think, to be able to do that. We're constantly looking. We don't feel the need to do anything in the near term. We want to make sure we keep our eye on the ball and any interesting assets that are out there, whether it's in the United States, in China, or elsewhere. We spend a lot of time scouring the universe.
Particularly in China, given its expertise in cell therapy.
OK. The next major topic, AI. How are you currently leveraging AI? Are you thinking about AI's future disruption potential?
Yeah. You know we are going to have to evolve. Every company that wants to compete is going to have to evolve and use AI effectively. We're probably in an adopt, not invent category where we are using AI to help our efficiency and our effectiveness. We do it in a very careful way where we'll often start with a pilot, set metrics, assess, and then expand as we see that it's actually adding value. There are places where it can be used, for example, for review of contracts and even the development and initial drafting of regulatory documents. It can be used for HCP engagement, for example, and tracking that in a much more effective and efficient way. Research design, obviously, image analysis, are just a few ways.
I would say we are looking to use it across the organization in ways where we can demonstrate that it's helping us with efficiency and effectiveness.
Are you seeing it being leveraged more on the manufacturing side or on the maybe R&D side?
I would say for us, probably more on the R&D side. We do have a complete paperless facility. Our manufacturing facility is state-of-the-art, completely digitized, and really made to be as protected from human error as possible. I would say we're probably using AI more on the R&D side.
Helpful. Last question, just in regards to potentially what's been most impactful from the regulatory side. Would you say it's the FDA, MFN, or tariffs?
Charlie, I might disagree on this. I would say we're focused acutely on FDA because we're obviously right in the middle of pivotal trials and BLA submission. I would say very fortunately for us, we got our regulatory meetings and our end of phase one and meetings required to start these pivotal trials with no issues. We're in good position there, although we continue to watch that closely. MFN and tariffs?
Once we agree, I think it's FDA.
Great. Lynn and Charlie, thank you very much for joining me today.
All right.
Thank you.
Thank you.