Good morning, everyone, and thank you for joining us at the second day of the Needham Healthcare Conference. My name is Gil Blum, and I'm a Senior Biotech Analyst here at Needham & Company, and I cover the cell and gene therapy space. It is my pleasure to have with me today Lynn Seely, the CEO of Lyell Biopharma, or is it Immunopharma now? Immunopharma. Lyell Immunopharma to discuss their very exciting programs, specifically in the CAR T space. Very happy to have you here, Lynn. It's good to continue to see some efforts in this space, despite certain investor sentiments. Maybe just starting with a broad overview of the company and its lead assets. Sure. Well, thank you Gil, for inviting me. Yes, I think investor sentiment is clearly changing in the CAR T-cell therapy space. For those of you who don't know Lyell Immunopharma is a late clinical-stage cell therapy company really focused on bringing next-generation cell therapies to patients, both with hematologic malignancies as well as solid tumors. We have two programs in clinical development for large markets. The first is ronde-cel. This is a dual-targeting CD19/CD20 CAR T-cell therapy, which we have really designed to replace the CD19 CAR T-cell therapies. We know this is an established $3 billion marketplace, but it needs better therapies. Ronde-cel has been very rationally designed to bring higher and more durable, lasting complete responses. We are currently in two pivotal trials for ronde-cel. One is a single-arm fast-to-approval study in the third-line setting, and the other is a first-of-its-kind, head-to-head randomized phase III CAR T-cell therapy trial of ronde-cel versus investigator's choice of one of the two leading CAR T-cell CD19 CAR T-cell therapies. These programs are well underway, and we're very excited about that. In addition, we have a very novel next-generation CAR T-cell therapy for metastatic colorectal cancer. This is a program that is in phase I dose escalation in the United States, but it's based on a program invented in China that has already shown very nice clinical activity, both in China and in the US. I'm excited to tell you about both of those. Lastly, one thing that you should know about Lyell is that we have our own manufacturing center that is capable of commercial launch. We are, as we speak, manufacturing with our commercial manufacturing process for ronde-cel, so in many ways, we're very fortunate to control our own destiny when it comes to manufacturing. Excellent. Let's start with ronde-cel. A first look as it relates to how do you feel it's differentiated from the standard of care CAR Ts, the approved ones? Yeah. It was designed very rationally from the beginning to be differentiated and to bring a new value proposition for patients over and above the CD19 CARs. The first feature of ronde-cel that really differentiates it is the fact that it has two targets instead of just one. It has CD19, and it has CD19 at full potency, but it also has CD20. It's designed as this Tandem CAR to have full potency at either CD19 or CD20. This is important for two reasons. First, it kind of makes sense that if you're targeting two antigens, you can drive more complete responses. That's because some malignant B cells have low or no CD19 and might not respond to the current CD19 CARs, but they do have CD20, and so would respond to a dual targeting 19/20 CAR. One of the key mechanisms of escape from CAR T-cell therapy is in fact antigen loss. These malignant cancer cells can drop an antigen like CD19, but it's much more difficult for them to drop two antigens and sort of escape the benefit of a dual targeted CAR. That's not all. Our CAR is differentiated because we have a very special manufacturing process where we enrich for naive and central memory T cells. These are, we call them more fit T cells, so that they basically can persist longer, have a little softer adverse profile, and actually expand quite nicely. The combination of this dual targeting and the fact that we have more naive T cells in our cell product, we think is very important combination to bring the outcomes that we're seeing with ronde-cel. One really important aspect of your development program is this really aggressive head-to-head study where you're pitting CAR Ts against each other. I think this is the first such study in this space. What makes you confident that you can outperform on efficacy of the existing standard of care CAR Ts, specifically Breyanzi, that has some pretty decent long-term follow-up? It is a bold strategy. Traditionally in development, you're taught not to run head-to-head studies. In this case, it's the right study to do, and it's for several reasons. First and foremost, we're developing products for patients. If we expect physicians to change their prescribing behavior from CD19 to 19/20s, and we believe this is the next-generation CAR T-cell therapy, we need to provide the data to support that. We do believe this is the next generation. We do believe the data are better. As always, we are very science-driven. We understand the biology here and the mechanism, as we just talked about. It makes intuitive sense biologically that a 19/20 could drive more complete responses with longer duration of response. We've generated data. This product, we've presented data in an oral presentation at ASH last year in the third and later line setting, where we've shown 93% overall response rate, 76% complete response rate, and very importantly, a median progression-free survival of 18 months, data which are significantly improved compared to the third line data from the CD19 CAR. That's the first set of data. We've also presented data in the second line in a very difficult to treat patient population, patients who have failed even frontline Chemotherapy. They never even responded to Chemotherapy. These are primary refractory patients. There again, we're seeing very nice complete response rates and duration of response, better significantly than what has been presented or published for the CD19 CARs. When we put this data together, we feel very confident in our design of this head-to-head study, and I think we're looking to bring value to patients not only in outcomes, better complete response, longer duration of response, better event-free survival, and also the safety profile. I think we know that the currently approved CD19 CARs have some neurotoxicity. They have some grade three or higher CRS, and we're looking to bring a better safety profile as well to allow for more outpatient administration. Would you say that copying is a form of flattery? What are your views on the announced head-to-head study that's pitting Kite's own dual targeting of CAR T-753 versus their own YESCARTA? Do you feel this complicates the therapeutic landscape in the second line? I feel like at Lyell, we are leading with ronde-cel, and we, more than a year ago, started this trial. We are currently well on our way in dosing patients as we speak. This is something that we have been working on for quite some time, leading the field. Of course, if you have this beautiful study design, others may have to copy, and it sounds like Kite Gilead is beginning to work on their trial. Again, they're substantially behind and being first matters in this space. I think being able to bring out our data and to get there first with our single-arm pivotal trial, we hope to be the first CD19, CD20 CAR T-cell therapy approved, gives us a substantial advantage because with the safety data that we're showing to date and the outcomes, we think we have a really nice opportunity to supplant the currently approved CD19 CARs. It's going to take a lot to supplant the data that we're bringing, because there's not much room left in terms of efficacy or safety benefit. Maybe a more pointed question there. The details matter, and you guys' control arm is both assets, while Kite's going to just go against their own YESCARTA, which we already have an idea has some issues. I'm just wondering what the therapeutic landscape may look like with the separate labels, and how would physicians and payers navigate that? Well, I think we've designed our study to be as real-world and inclusive as possible. We know that physicians today are choosing, some use Breyanzi, some use YESCARTA, some use both, depending upon the patient. In our trial, patients come in, and then they're either randomized to ronde-cel, our CD19/CD20, or investigator's choice of either YESCARTA or Breyanzi, so that the physician can do what the physician wants to do, and it makes it very real-world for them. I think so it really will give them the data that they need to make these decisions by looking at both, right? We believe that we're going to be able to show superiority despite including both products in the control arm. We think that's a real advantage to our product. I think complexity, I don't know. We've designed our trial to bring data to the patient and physicians that they're looking for, and we think that that will be quite clarifying, quite frankly. The beauty of the randomized controlled head-to-head trial is that patients are stratified. We're not going to have to look at cross-trial comparisons. We're not going to have to worry about what was done many years ago. We're going to be able to look at this trial and say, "Is ronde-cel superior to the approved CD19 CARs or not?" That's what doctors and patients want to know. It's bold, but it's also the right thing to do. When you think about it commercially, it's going to be very easy to take these data out. These are data-driven physicians, and they're going to be able to see very clear data, or not, based upon the superiority of this product. If we're not superior, we shouldn't be on the market. We believe that the science and the data clearly indicate that we have a great opportunity here. I do want to spend a second on the safety profile. This is an important selling point for products and some so-called 2nd-gen products in general. There's no high-grade CRS, but there's still a low level of high-grade ICANS. Is that a barrier for adoption in a community setting? How do physicians treat a low incidence of high-grade ICANS? Yeah. We've seen, as you pointed out, no Grade 3 or higher CRS, cytokine release syndrome, in our program. We have seen less than 5% Grade 3 or higher ICANS. This is generally short-lived and readily treatable with current standard of treatment. I think this is being administered in the outpatient setting today and in our pivotal trials. We think it's very amenable to outpatient administration. I think one thing, this is uncommon, right? I think one of the things that we know is physicians are more and more getting used to things like how to treat and diagnose ICANS, as well as CRS. We don't think this is going to be any barrier to outpatient administration. In fact, it's so low, we think it's going to be a great advantage of our product. Yes, all patients given CAR T-cell therapy need to be monitored, certainly in the first couple of weeks after treatment. Again, this is a very low incidence. We think the safety profile is quite favorable, versus what we're seeing with CD19 CARs. You currently allow bridging in your studies. This is not something that was common in many CAR T studies. I think in the past, it was only steroids, at least for a few of these. Any specific comments there? It feels more real-world. I think that's probably the takeaway here. That's right. In the past, different companies have done different things. We feel like allowing bridging therapy is important, because we want any patient who's eligible for CAR to be able to come into our study. Some patients are progressing rapidly, right? They can't wait for CAR manufacturing without, for example, bridging therapy. By excluding bridging therapy, you're excluding a group of patients that could potentially benefit from the product. We are allowing bridging therapy in our trial, and we think that's an advantage of the trial design. Well, I know we did this a little backwards. Going back to your third-line study, what would you say the commercial strategy is here? It's a single-arm accelerated approval study. I think this third-line study is incredibly important and probably more important than most people realize. Let me tell you why. First of all, the data which I described to you, but let me do so in a little bit more detail, are quite compelling. We have a 93% overall response rate with a 76% complete response rate. That remission rate or complete response rate compares to 50% complete response rate for the currently approved CD19 CARs. More importantly, the median progression-free survival, which is the time at which 50% of patients have progressed or died, in the CD19 CARs is six to seven months. It's 18 months as of our ASH presentation last year. That's a big difference. We know that the prescribers of CAR T-cell therapy, they're very data-driven, and so they may be loyal to CAR and believe in CAR because of its curative intent. They will change CARs based upon safety or efficacy. With ronde-cel, we intend to bring both. Okay? We want to get into this marketplace as fast as possible and begin this process of switching from the CD19 CARs. It turns out that in the third or later line, which is what our first approval is planned to be in, is a much larger market than people think, we believe. The reason I say that is because we know from a series from Memorial Sloan Kettering, that patients who undergo apheresis, so 50% of patients who undergo apheresis for CAR have already seen two regimens of chemotherapy. Now, physicians may count lines a little bit differently, but really, it's two lines of chemotherapy. This could be a third-line patient if you are counting on-label for our approved 19/20. We think this is a 6,000 to 7,000 patient market opportunity, which is very important and will allow us to get this strong foothold. Commercially, being first, which we're currently in the lead in this space, is really important for us and we think gives us this commercial advantage. Because once we get there, what are you going to bring to switch us out? The primary endpoint of this trial is overall response rate. We're sort of sitting at north of 90%. That's going to be hard to make a meaningful benefit over. One of the challenges, and this is, well, easily figured out, is that there are quite a few patients who are theoretically eligible for CAR Ts, but if you only looked at the label, it's much, much, much narrower than that. How do you bridge this gap as it relates to patients who should be eligible, but are currently not receiving therapy? Yeah. That's a great question. The field has changed a lot, right? It used to be we talked about transplant eligible and transplant ineligible. Those days are kind of gone, right? One of the things that Lyell we're doing with ronde-cel is we don't have any upper age limit. We've successfully treated 85, 87-year-olds, and this is important in large B-cell lymphoma because these patients have a median age of 65. That means there are a lot of patients older than 65 who need this treatment. We want to make it as available as we can. For example, in our head-to-head trial, we're taking patients of any age who have primary refractory disease, early relapse disease, late relapse disease, if you have bridging therapy or not bridging therapy. We're really trying to give this a broad label. If you're eligible for CAR, you can be on-label, is sort of our ultimate goal. Just to remind everyone, the timelines as it relates to data disclosures from the pivotal study and when its final readout is expected. Yeah. This third or later-line study, we call it PINNACLE. We're going to be having a significant data update in the second half of this year, which will really be the last look at the data before the pivotal trial data comes. We think is a real opportunity to get a good look at what it will be. The data, the pivotal data itself, the data we'll use for BLA submission will be available. Expectation is mid-next year, so coming very soon, with the BLA submission to follow next year. This is upon us. We're super excited and we think this is a really meaningful commercial opportunity, which is going to give us every opportunity to be first-in-class, which we think is going to be a big deal in this marketplace. I want to touch on other competitive dynamics, recent readout just yesterday from Allogene in the frontline setting consolidation, really interesting idea where you can use an allogeneic CAR T for a mop-up. My question is, let's say it's approved, this consolidation, does this change the type of patients that might come down and receive your product? Yeah. You're referring to the data put out by Allogene yesterday with their product, cema-cel, which they're evaluating as consolidation therapy after frontline therapy in MRD-positive patients, right? First and foremost, I'm always pleased to see a cell therapy company have positive data, so that's great for the field and hopefully at some point will be great for patients. I think what we have to look at, this was a futility analysis, so the goal was to say whether or not the company should continue to enroll patients. Now, it wasn't an efficacy analysis. It wasn't the primary endpoint of the study. It's early days, right? I think there is some encouraging MRD positivity data, some safety data, but we're going to have to see how that translates in durability into the primary endpoint, which is a change in event-free or benefit to event-free survival. At Lyell, we are full-on believers in autologous CAR T-cell therapy. This has the potential for curative intent. We already have data showing that we have better complete responses and median progression-free survival that have been seen with the CD19 CARs. We are barreling forward. I think this idea, there's a long road to go to get, first of all, to the efficacy analysis for new allogeneic treatments, then we have to get MRD testing done. We have to change the practice, get consolidation therapy and sort of embedded into the community practice. Quite frankly, it's still a relatively small segment of the overall large B-cell lymphoma population, right? It's patients who are MRD positive with response after their first-line therapy. We don't know, they didn't say, but maybe it's 20%, 25% of patients. Maybe optimistically, half of those are going to get MRD testing. It's going to end up being maybe 12.5% of the patient population. We're not worried about it. I think the benefit of autologous is still very real, and if Allogene is available to increase accessibility of cell therapy for patients, that's a good thing. We don't think it in any way changes the outcome for ronde-cel. Great. Maybe a more real topic, because this is further down the line. We've talked to a lot of physicians over time, specifically on T-cell engagers, which have been kind of positioned in late-stage patients. Everyone kind of expects these to move forward. They've had some challenges, but I think it's a bit of a matter of time. How do you think that changes the type of patient that you get at later line? Yeah. Gil always asks the hard questions. Bispecifics are here. They are being evaluated in the front line, and I think I'm always very focused on patients, right? What's in the best interest of patients? I think what patients typically want and that we hear consistently is a one-time treatment that gets them back to their normal lives with disease-free, treatment-free periods. That's exactly what CAR T-cell therapy is designed to do. That's not what bispecific therapy does. Now, there's a role for Bispecifics, absolutely. I think many people who know the most about CAR T-cell therapy and Bispecifics believe, quite frankly, that Bispecifics may harm actually the benefit of CAR T-cell therapy, and it may be in the patient's best interest to get CAR T-cell therapy before Bispecifics. Yes, they may add some benefit in the front line, but the current chemotherapies work quite well, and it may be better actually to use Bispecifics after CAR T-cell therapy. This is going to be evolving over time. The Bispecifics are here, I agree, but I think in no way they've been able to show the sorts of data that, for example, ronde-cel is showing. The onus is on us is to get our trial data out there and completed so that patients can see the choice that they have. Just focusing for a second on manufacturing before we shift to solid tumors, just how scalable is ronde-cel manufacturing, and what level of capital investment are you guys putting in? Also, how should we think about margins because most cell therapies in the beginning are negative margins? Great question. Lyell's quite unusual here in the sense that we have already invested years ago in building a commercial manufacturing center. That sort of sunk cost, we have now control of our own destiny. This manufacturing center is staffed with people, highly experienced in cell therapy manufacturing. We are running today our commercial manufacturing process for ronde-cel. We're capable of commercial launch, well into commercial launch. We can make more than 1,200 doses per year at that facility. We are in a very good position to control our own destiny. We're currently making all of our clinical trial material there, and then we'll continue on into commercial launch. Our process is very reliable and robust. We have more than a 95% success rate. It's a simple process. The vein-to-site time is 16 days, which is quite competitive with Kite Gilead and better, quite frankly, than BMS. The process is simple. Fortunately for us, the cost of goods is very reasonable and it will only get better over time. We're estimating something like 20% of overall for cost of goods. We're in a very good position for manufacturing. Again, I'm tremendously grateful for the manufacturing team that we have at Lyell. Great. I do want to spend some time here on the LYL273 program. It's a very interesting program. Maybe just start with the unique mechanism of action for this particular CAR T. Yeah. We've talked a lot about ronde-cel, which is the sort of our late stage on the way to pivotal and I think is really our lead program. Now we have this very potentially transformative program coming up behind, which is in the clinic, and we call it LYL273. It's a Guanylyl Cyclase C-targeted CAR with a novel mechanism which Gil's alluding to. GCC is expressed on more than 95% of colorectal cancers in their metastases, so very highly expressed. We don't need a biomarker for this. Also, a lot of people don't know it's expressed on the majority of pancreatic cancer. It's a really great target. Cell therapy for solid tumors had kind of a rough road, and just a great target alone is sort of not sufficient. This was invented in China, and the thinking was, a target is not enough. You have to couple that CAR with something else to overcome some of the barriers we've seen. The biggest barrier in solid tumor is to get enough cell expansion to allow the CAR T-cells to infiltrate into the cancer. These cancers are oftentimes very cold. You also have to flip the hostile tumor and microenvironment. You have to warm it up, so to speak. Here's the concept. This GCC-targeted CAR, which is a great colorectal CAR target, is coupled with CD19. Well, that's unusual, right, because that's a B-cell target? What happens is these CD19 CARs are also engineered to release cytokines. As you infuse these cells into patients, the CD19 CARs get activated when they hit the B-cells, start to release cytokines. There are these very special doublet cells which have both CD19 and GCC CARs, which then expand and release cytokines. These increased cell numbers can infiltrate into the tumor, continue to release cytokines, and help warm up this hostile tumor microenvironment. Of course, the GCC CARs expand and persist over a very long period of time. Together, this is giving us a window, I think, into how to treat solid tumors writ large. It gives us this opportunity to get the right cell expansion, and with this very specific cytokine secretion, help get a better immune response in the solid tumor itself. Novel mechanism. Fortunately, the manufacturing is quite straightforward. The bottom line is this is in phase I study in the US, and we're seeing very nice clinical activity. Maybe a bit of a general question here. One of the off-tumor, on-target effects is B-cell aplasia. Mm-hmm. Do you expect any pushback from the agency as it relates to elimination of a cell population in a, well, sick individual, but that's not the target cell? Yeah, that's a fair comment. As you know, these patients have a life expectancy of 12 months or less. These patients are dying. The B-cell, it is a true statement that the B-cell does get targeted, but it's very short-lived. Maybe a month or so in duration, they start to repopulate relatively quickly. There's almost like this CD19 spike in cell expansion in the CAR T-cells, and then it tends to dwindle away, and the B-cells repopulate. We haven't seen any pushback or issues with B-cell aplasia because it's relatively short-lived. Also a related question. GCC targeting has been attempted. It's not easy. There is some expression in the gut, which leads to diarrhea. Mm-hmm. can be severe. I know you guys have seen some of that in your own studies. Can you walk us through some of the mitigation strategies there? Yes. That is absolutely a fair comment. GCC tends to be overexpressed in cancer cells, but is expressed at low levels in normal gut. This is a potential on-target off-tumor toxicity that we have to be very careful about. We have seen some GI toxicity, so what's been implemented into the program is a quite robust prophylactic regimen, as well as a very standard treatment management plan to work with that. When we brought on this program at the end of last year, we presented data in about 12 patients. That prophylactic regimen had just been sort of implemented, and we've sort of said that since then, we've enrolled another seven patients, including escalation to dose level three without any dose-limiting toxicity. That at least gives you an idea that the program is continuing, and that the diarrhea is being managed. This is a side effect to watch. It's one of the reasons we said we're going to be doing a safety update in the first half to really let people know how that safety management plan is working. Great. Just to remind our viewers what the efficacy data looks like in your first couple of cohorts, and how does that compare to existing standard care or even emerging therapies? Yeah. Maybe I'll start with emerging therapies, which unfortunately are not what we might hope for the patients. I would say in particular, because this is a disease that is surging in younger people, and we're seeing patients more and more frequently in their 40s, 30s. I mean, it's a devastating disease. One might imagine CAR T-cell therapy, a one-and-done treatment, for these, particularly these younger patients, is incredibly important so they can get back to their families, their work. The current therapies that are approved in the third or later line for metastatic colorectal cancer, which is what we're currently studying, has single-digit response rates, like 6% or less. The median progression-free survival is six months or less, and the median overall survival is less than 12 months. We need better therapies. The bar for a response rate for this CAR T-cell therapy is anything 20% above could be approvable, without much above a six-month PFS. I mean, very honestly. Anything more than that is, of course, even better. I would say, what have we seen so far? I think I mentioned that this product was invented in China. They ran a single center study in China, which was published in JAMA Oncology, where they studied it in Chinese patients and showed a 40% overall response rate and a 25 month or a two year median overall survival. They saw such promising results that the company brought the product to the US. They got an IND approved as they set up manufacturing, and they got some premier medical centers to participate with them, Dana-Farber Cancer Institute, the University of California, San Francisco, City of Hope, and the University of Colorado. At the time we last presented data, we had 12 patients, six at dose level one and six at dose level two. Across the two dose levels, saw about a 50% overall response rate with one patient in particular with a partial response, 100% partial response, that is now getting close to two years out from her initial treatment. An active CAR. I think we are continuing to optimize dose and regimen, and then, of course, it's incumbent on us to manage the safety profile. I think if we can do those things, this can move quite quickly, simply because, as I said, there's so little for these patients. Let's talk about what guidance you can provide as it relates to the data disclosures upcoming in this program. Yeah. We have two data disclosures this year. The first we've said will be sort of a company announcement. I mean, we just got this at the end of the last year, so there really wasn't time for major medical meetings in the first half. We did want to update on how that safety management plan is working. It will largely be a safety update. In the back half of the year, we intend hopefully to have a presentation, a major medical meeting where we can show more outcomes. Sounds very exciting. Maybe ESMO, maybe. Always fishing for information, Gil. I think, again, this program can move quite rapidly, and our goal is to get the data we need to move it to the regulators to talk about what a pivotal trial might look like. Maybe kind of a last comment as it relates to emerging therapeutics. We saw some interesting data on ADCs and others. There is a sense that there is maybe a cutoff at about 30% response rates. Yeah, given this is a CAR T, what we should really be looking for is probably long-term efficacy. Would you agree on that point? I think the good news about response rates is typically because they drop disease burden, they tend to also prolong outcomes for patients. I think it would be great to see nice response rates because that's something that, of course, is very helpful for patients and also it makes it easier on clinical trial design. I think the fact that we're seeing response rates is something that is very helpful to us. I think right now the best drug approved in the third or later line has a median progression-free survival of six months. Yes, we need something longer than that. The longer, the better for patients, no question about it. So I think that's what the agency, if we can see some meaningful response rates that have some durability, which as I said, we've already got patients that are showing that, then I think that can be very helpful to us. But the data needs to mature, for sure. Last couple of points, cash runway, cash position. Yeah. So as of our last Q, we had $247 million, or I should say as of our 10-K. We took a second tranche of $100 million private placement we had of $50 million. So that gives us a cash runway well into Q2 next year. Cool. Kind of as a last one, anything you would like to highlight as it relates to what you think investors are missing in the story or just open-ended? Yeah. I would say I think the most important thing investors are missing is that ronde-cel is in the lead for the next generation CD19/CD20 class, with a third or later line approval that is coming very soon. I think what they're missing is this is a much bigger market potential than people appreciate because of this fact that even despite how lines are counted, 50% of patients have received two regimens of chemotherapy before they undergo apheresis for CAR. That's a really important point, and we think there's a significant number of patients out there, and it allows us to be first and get this stronghold as the next generation CD19/CD20. It's going to be much harder to replace us because of the data set that we're bringing. We think this third-line lead that we have is really important and that we're looking forward to executing on that. Very fun. Thank you very much for attending today. Well, thanks for having me. I really appreciate it.