Hello, everyone. My name is Mitchell Kapoor. I'm a senior biotech analyst at HC Wainwright. Thank you all for joining our HC Wainwright at Home series. Today, I have the lucky pleasure of welcoming Lyell. From the management team, we have Lynn Seely, Chief Executive Officer, and Charlie Newton, Chief Financial Officer. Thank you both for joining us today. Thanks for having us. Great. So, you know, we're going to have an in-depth discussion about the new asset, the new Lyell, and kind of where we stand. But, you know, just to start us off, if you could just give us an overview of the company for those who may not be familiar with the story. Sure. Lyell Immunopharma is a cell therapy company really designed to bring next-generation cell therapy to patients with cancer. We are in both hematologic malignancies as well as developing next-generation CAR T- cell therapies for solid tumors. Our lead program is an autologous CAR T- cell therapy. It is a dual-targeting CD19, CD20 CAR T -cell therapy, which is really designed very specifically to bring patients more complete responses and longer periods in remission, so longer disease-free, treatment-free intervals, which is really what they are looking for and even the potential hope for cure. We are on a mission to develop these next-generation CAR T- cell therapies. We just returned from the International Conference on Malignant Lymphoma, where we presented data from our lead program, this dual-targeting CD19/20 CAR, and we're really able to show, we think, an important step forward with this CD19/20 therapy in a way that we hope can lead to some disruption in the CD19 marketplace because we believe we're bringing to patients better clinical benefit, but at the same time with a safety profile which allows for outpatient administration and so is quite safe. We are very pleased that we've been awarded Regenerative Medicine Advanced Therapy for this program by the FDA, and we have recently announced that we're in pivotal or registrational clinical trials. We have had our end of phase I meeting and are barreling forward with a single-arm trial in the third-line setting of relapsed refractory lymphoma, large B -cell lymphoma, for approval. It's a single-arm trial. We've also said publicly that we'll be starting a trial for registration in the second line. Full steam ahead here at Lyell with our next-generation CAR T- cell therapies, particularly for aggressive relapsed refractory large B- cell lymphoma. Great. That's a wonderful overview. Specifically on 314, could you talk about the design and the rationale for dual-targeting of CD19/CD20 amid the commercial CD19 CAR Ts in the development landscape? What's the expected differentiation over those CD19 CAR T therapies? Yeah. So I think many of you may know that CAR T- cell therapy, specifically CD19 CAR T- cell therapy, has really made a major impact in the treatment of lymphoma and, you know, really changed it from a day of chemotherapy with very limited response rates to CAR T- cell therapy with better response rates. It is important to note that they do not work in all patients. In fact, 50% of patients in the third line, where our initial focus is, do not respond at all. There is a real need for better therapies. Our CD19/20 dual-targeting CAR was very specifically designed to bring more complete responses and longer remission or longer duration of those responses. It does it, and achieves it in two ways. These large B- cell lymphomas are caused by malignant B- cells, and those B -cells have targets. They have CD19, and they also have CD20, and they're heterogeneous. Some malignant B-c ells have a lot of CD19 and maybe not so much CD20. Some have a lot of CD20 and not so much CD19. When you bring two targets with your CAR T- cell, both CD19 and CD20, you're more likely to get complete responses. The dual-targeting is important. Our particular construct was designed very carefully to be a true or gated CAR, which means it brings full potency at CD19 or full potency at CD20. We basically have double the chance of bringing and killing these malignant B- cells. The second thing that's important about our product is because we have two antigens that we're targeting, it's much harder for these cancer cells to escape therapy. They can drop these antigens in an attempt to outsmart the treatment, but when there's two of them, it's much more difficult. One of the key reasons we don't see as long of duration of response with the CD19 CARs as we might like is because the malignant B cells can drop CD19, but it's much harder for them to evolve to the point where they drop both CD19 and CD20. This dual-targeting, we believe, is bringing more complete responses and longer duration of response. We have a third secret sauce, if you will, and that when we manufacture our cells, we select for what's called CD62L positive cells. What this means, it's a marker that enriches our cell product for naive T- cells. It is well established in the field that naive T- cells in the final drug product can actually improve outcomes for patients. We believe it leads to better persistence of the cells, better engraftment, and overall better responses for patients. This was shown in an axi-cel ZUMA-7 study where they were able to look at patients who had more naive T -cells in their final product versus those who had less, and those patients who had more naive T- cells had better overall survival. We have a very high proportion of naive T- cells in our final CAR T- cell product. This product, very simply put, was rationally designed, very carefully designed to bring better complete responses and longer duration of response over and above the CD19 CAR T- cell therapies. That's a great overview of the next generation of where CAR Ts are moving in this space. Just jumping into the data, you recently shared updated data for both third-line LBCL and second-line LBCL for 314. Can you recap that for us, talk about the different patient demographics, all the things that are important to know about what you recently presented? Yeah, sure. Maybe I'll take a little bit of a step back. I think the CD19s have sort of been approved. They've taken a very strong position in the marketplace. As we talked before, there's limitations with their data. As we've said, 50% of patients in the third line don't get a complete response. The time to progression, you know, really six to seven, about 50% of patients will progress or die within the six to seven months. Even those patients who do get the CD19 CARs, they're not getting this duration of response. The field has really made quite a step change in just the very recent past. As you alluded to, we just returned from the International Conference on Malignant Lymphoma, where they had a session. We were able to present our data. There were some other companies presented data, and it was becoming very clear that the CD19/20s are moving forward. I'll lead with our data, which gives you an example why. In the third-line setting, overall, we presented data from 51 patients. In the third-line setting, we showed an 88% overall response rate with a 72% complete response rate. That 72% compares to what we've seen previously with CD19 CARs of about 50%. Going into remission is important, but what patients really care about is the duration of the remission. We were able to show that of those patients who went into complete response, 71% of them remained in complete response at six months. If you go back to the CD19 CARs, that number is about 40%, so substantially better. We're really pleased with those data. We now have patients swimming or remaining in remission for the past 12 months and even 15 months. Those data are really looking quite positive. Again, all in the setting of a safety profile, which allows outpatient administration. In the second line, this was the first time we've presented data in the second-line setting. It's really important to note that our patients in the second-line setting were really sick patients. One of the things that we've done, because we believe we have this new design and something that can maybe be well tolerated by patients, we don't have an upper age limit. Patients with large B- cell lymphoma tend to be older. We've allowed all patients of an upper age limit to come in as long as they meet other eligibility criteria. Most of the patients that were enrolled in our trial, in fact, 82% of those in the second line had primary refractory disease. That is important to know because primary refractory disease is the hardest disease to treat. They have not responded to front-line therapy at all, and now they have come on to our treatment. What we found is the overall response rate was 91% in those patients, and 70% of patients with primary refractory disease went into complete response. The data was really quite well received by the experts that we were able to share with at Lugano, and we think compare really favorably. On top of all of that, again, as I said, this was achieved with a nice safety profile appropriate for outpatient administration. Great. Okay. I know you touched upon comparison to YESCARTA, but just, you know, as we focus on the cross-trial comparisons, which are always limited, could you help us understand a little bit more in detail how the 314 data compares, albeit early, to some of the data we've seen from the other approved CAR Ts? One of the focal points is the ZUMA- 1 study, but anything else you'd like to highlight that can help us put this in context for third line? Currently today, there are two CD19 CARs which are out in the marketplace. Yescarta or axi-cel is the market leader, and Breyanzi or liso-cel is sort of rising in market share. They are a little bit different, I would say. When you look in the third line, let's start there. In the third line, these two products, these two CD19 CARs, have very similar benefit to patients. About 50% in each of them bring patients into complete response. As I said, we had 72%. Both of them have maintained patients who achieve a complete response, incomplete response at about 40%. We had 71%. I think comparing very favorably to both axi-cel and liso-cel in the third line. I think the other issue, particularly with the market leader Yescarta, is some neurotoxicity. The rate of ICANS, and in particular, grade 3 ICANS for axi-cel is about, in the third line, about 31%. That is a, you know, a problem for them. We were able to show substantially lower ICANS, and again, amenable to outpatient therapy. We think in the third line, the data stack up very, very favorably. In the second line, it is still early days, but the fact that we have really broadened the patient population. The only place really to compare Yescarta in their second-line program for approval, they really limited their patient population. They limited to younger patients. You could not be really above 75. They also did not allow bridging therapy. What is bridging therapy? Bridging therapy is what you use for patients from, you know, when they are sort of awaiting their CAR therapy. If you're going to, you know, it takes about, in our case, it takes about 16 days to manufacture the CAR and get it to the site. Patients are treated with chemotherapy oftentimes or radiation therapy to hold them until they can get their CAR T- cell therapy. In the ZUMA- 7 trial, which was the second-line trial for AXA cell, they did not allow bridging therapy. By definition, they selected for patients, or they only allowed like steroids, which is a light bridging therapy. It selected for less sick patients. In this study where we just presented data, we had older patients. We had the vast majority had primary refractory disease. They had very high volume disease, so very sick patients. There we were able to show a 91% overall response rate and a 64% complete response rate. We can compare that in the Breyanzi setting because they also had an older, sicker patient population enrolled into the pilot study, which was a single-arm study they used for approval. There in primary refractory patients, the complete response rate was 46% compared to our 64%. We believe we're consistently showing this benefit above and beyond the CD19 CAR T-c ell therapy, again, all in the setting of an acceptable safety profile. I think this is really what patients have been looking for in this space. What we're sort of seeing is this really switch of the field, and this data all just came out. What's so exciting about where we are is the CD19 approved therapies have brought value to patients, but now we think the next generation is very clearly the CD19/20s. Great. Yeah. So that's helpful to provide this context to change the landscape. I know that there are others out there trying to also change the landscape. You know, could we just touch upon, I think one of those is pretty interesting early on is KITE-363 in LBCL. Could you talk about the differences in their program, the construct, patient characteristics, study design, or anything else you think is helpful that may distinguish 314? Also just, you know, talk about some of the safety benefits that you all are seeing versus. Yeah. I think it's telling, isn't it, that Kite Gilead, who manufactures Yescarta, is also developing a CD19/20. It says it's not just Lyell and some acute opinion leaders who believe the CD19/20 is the next generation, but Kite Gilead, in fact, believes the same. They also presented the very first data coming out of their CD19/20 program at ASCO, and then again at this European meeting we were referring to. Their construct is different from ours. We have what we call a tandem CAR. It's one CAR that has both CD19 and CD20 that are at full potency, so pretty simple to manufacture. They have two CARs, or what they call a bisystronic CAR. They express a CD19 CAR, which is actually Yescarta, so it's AXA cell, as well as a CD20. It's a little bit different from ours. I think what's interesting is I would say the efficacy, the benefit is similar. It's hard, it's early days, and there are not a lot of patients. I would say in general, they are also showing a clear advantage over the CD19 CARs. Where I think there may be some issues to talk about there really is in the safety profile. I think if you look, for example, at any patient, there are sort of two safety or side effects that people look at with CAR T -cell therapy. One is called cytokine release syndrome, and that's sort of an inflammatory response to treatment. I think 92% of patients who received the Kite Gilead product developed CRS in comparison with 57% of the LYL 314 patients. I think that's a difference in and of itself. Then similarly, with respect to ICANS, which is a neurotoxicity syndrome that we talked about, 46% of the Gilead Kite patients with their CD19/20 patients developed ICANS, 21% of our patients. I think you can see that there are some differences emerging in the safety profile. Again, it's validating in two ways for LYL 314 that Kite Gilead agrees that CD19/20 is the next generation and also that they also showed benefit above and beyond what the CD19s have shown. Again, we feel like we're in good position there. Where we have, I think, a differentiated advantage is that we are selecting our cells for the CD62L naive T- cells, which gives us, I think, an advantage in terms of duration of response. It's early days, so we have more duration, I think, than in more patients than they have. I think the other thing to say is that we are in pivotal trials. We are moving forward rapidly. That's very helpful. I think it's also, you know, can be definitely seen as a positive to have a validating competitor like Gilead and Kite working on the same modality. Great. Are there any other competitors, you know, that you're watching in the space or anything else, you know, that you think may be equally as interesting as the 363 program? Yes. There is another competitor. I think, as always, it's again another sign that we're on the right track. Johnson & Johnson also has licensed from China a CD19/20 CAR. This CAR is highly similar to the CAR that we have. It was initially developed in China, and then they licensed it, and they presented the first data from their work at J&J where they have patients both in the U.S., Europe, and Australia. I think there again, too, very similar benefit in terms of efficacy seen across patients. This is again a very validating situation that I think is going to be a bit of a race, but we feel like we're in a very good position. Quite frankly, we believe we have dominant intellectual property position because the intellectual property position for our product came out of UCLA. This was invented in the U.S. by a really excellent scientist at UCLA and patented in 2014 and predates anything else that's out there as far as we're aware. Okay. That's very helpful context. In light of all of these developments in the competitive landscape and the existing CD19 CAR Ts, could you help us understand in the third-line setting for 314, what is the benchmark to beat? You know, could you talk about that with respect to complete response, the durability of complete response? When do we start to see enough data to say this is, the durability is competitive, more competitive definitively than the standard of care as well? Yeah. It's a great question. We'll just start with the third line. I think, you know, we presented our first data in December last year. This was now an updated data. The durability is really starting to come along quite nicely. As I said, we're in pivotal trials, a single-arm pivotal trial. What will be used for the primary endpoint of that trial is going to be overall response rate. Our overall response rate is 88% to date. That's what we just presented at this recent conference. Again, in comparison, the overall response rate of the CD19 CARs is in both AXA cell and Lysocell almost the same, 70%, approximately 70%. You can see there's a substantial benefit already. I think that's why we're being allowed to do a single-arm trial for approval because we're showing robust benefit over and above. On the complete response side, they've shown about 50%. We're showing 72%. Again, not trivial. In terms of the overall response and the complete response, we'll need to show benefit over and above what they've shown at 70% and 50%. We think we're well on our way to doing that. Now, durability is harder. The way we sort of look at that is you can see very clearly from Yescarta, the market leader, as well as Breyanzi, that those patients who remain in complete response through six months tend to have durable responses. Those are the ones that really see the best benefit for the product. We really use that as sort of the sign that we're getting the sort of duration that we want. That is why we are so pleased to report that 71% of our patients who achieve complete response remained in complete response at six months. That is what the agency is going to be looking for when we bring our product for approval. They are going to be looking at the overall response rate, the complete response, and then that duration of response, particularly six months and beyond. We think we are in excellent position there with the data we already have on hand. Of course, we are going to have to enroll about 120 patients total to get to about 100 patients to submit to them. We think we are in good position in the third line. Got it. Okay. If I'm understanding correctly, just to make sure, the six-month complete responses from the approved CAR Ts correlate well to the durability in the long term for those CRs. That is why you're using that as a current benchmark of how successful 314 could be. Yes, that's exactly right. They have about 40% of patients remain in CR at six months. We're at 70%. Got it. Yeah. That's not a small benefit. Right. Okay. Very helpful. The pivotal trial design you touched on a bit for third line is a single-arm design. Can you discuss a bit about that trial design and how the FDA and you all landed upon this trial? Sure. The most important thing is we provided our data to the FDA. They gave us Regenerative Medicine Advanced Therapy designation. RMAT designation really is similar to breakthrough therapy for cell and gene therapy. Breakthrough therapy is more on small molecules and Regenerative Medicine Advanced Therapy. That is a sign that the agency is very impressed with our early data to date. That gives us an opportunity to have more frequent and higher priority meetings with them, which is great. We have already had our end of phase I meeting with them, and it aligned on the design of the third line study for approval, which is the single-arm study. We agreed on dose, safety monitoring, this idea of outpatient dosing, and then again, the primary endpoint of overall response rate and also duration of response. We are in a good place there. What's important to know about this is this is a seamless phase I/II design. The study that's been ongoing will be the pivotal study. We've got a cohort of third-line patients that we've been enrolling in the phase I/II study. That's just going to seamlessly become the pivotal trial. Those sites that are already up and going and enrolling are going to continue to enroll. To To speed it up, to accelerate it, we are adding more centers. Right now, we have about 16 centers open, and we're going to be adding about 10 more centers to really accelerate the recruitment. Okay. Got it. You know, investors are always focused on timelines, especially whenever you have competitors in the race as well. Is there anything you can help us on, you know, how fast this pivotal trial could go in the third line? You know, what are some of the case scenarios, best case and base case, for how long these could take before you could file for approval? Maybe if you can't say specifically, you could draw some analogs to others that would help us as well. Yeah. We've said the number of patients, I think it's clear from, you know, we've got about, you know, we presented data on about 34 patients in the third line. We believe we'll be able to use many of those in this pivotal trial. A couple of them maybe not, but we believe we'll be able to use the majority of them as part of that. We need to complete enrollment. We're not giving precise guidance yet because we really want to get an idea of how these new centers we're bringing on are going to help us to give us a better idea. We are in pivotal trials. We're the only one who said publicly that we're in pivotal trials. We think that gives us an advantage. The other thing that gives us an advantage, quite frankly, and I'm super interested to see how this plays out, but you know there's a lot of changes afoot in the cell and gene therapy division at the FDA. One of the things they're talking about are these national priority review vouchers. When you think about our product, it was invented in America. It's been developed thus far in the United States, and it's manufactured in the United States. We think that it's for a high-end medical need with a substantial advance over the current therapy. We think we may have an option there. That's something that is designed to, you know, help us maintain an advantage in the U.S. for important new therapies by shortening the time to approval. What these national priority review vouchers are for is to allow the agency only one month to review. That can substantially shorten the overall time to approval. We're watching with great excitement, actually, to see if that's something that might be an advantage for us and our particular product. Certainly. Yeah. It sounds like an interesting advantage that you could potentially have. Great. Okay. Moving to second line, a lot to cover with the third line opportunity and then moving upstream to second line in healthier patients or maybe not, you know, obviously with the primary refractory population that you had mentioned. Can you walk us through kind of the opportunity, I guess, just to start in the second line? Whenever you have CAR Ts approved in the second line setting, the opportunities in second line versus third line, could you just talk about how that could play out for Lyell? You're initially going after third line, but then, you know, moving up to second line. Can you walk us through that strategy? Yeah. Maybe, Charlie, why don't I bring you into the conversation? You want to take that one? Sure. Yeah. Maybe I'll comment a little bit just on the size of the patient population there and the unmet need. If you look at DLBCL alone, that is, you know, depending upon the source you look at, 30,000 patients per year that are being diagnosed with DLBCL. Those patients are then treated with first-line therapy. R-CHOP is the most common therapy that is used in that first-line setting. Patients that progress from that setting into the second line is really where we're targeting. If you look at the studies that have been conducted to date on the percentage of patients that progress post-R-CHOP, it kind of ranges in the 40%-60% range. That is broken between the primary refractory, which Lynn alluded to, are kind of the most difficult to treat patients, early relapsers, and late relapsers. In the primary refractory, patient population is about 10%-20%. Early relapsers is kind of similarly in, call it the 10%-15% of those progressors. The late relapsers are about 20%-30%, which kind of gets you to that zip code 40%-60% of patients that then either do not respond or relapse following that first-line therapy. We mentioned the primary refractory as being the really difficult patient population to treat. We are not limiting ourselves to that patient population. We only underscore it because it is such a challenging setting to show efficacy, and we had such strong efficacy there. We really believe that entire second-line patient population is what we will be targeting. Got it. That's very helpful. Okay. So although we have initial second-line data from the primary, mostly primary refractory population, not necessarily limiting it to that broadly in the second line. Yeah. Just to sort of add to that a little bit, I think it's this when you go back to sort of Yescarta, which you were talking about earlier. They really have limited their age range, sort of as we said, and sort of haven't included some of the sicker, more. They do have primary refractory patients, but they don't have older patients. I think one of the things that we've done is we've really broadened our inclusion criteria so we can capture more of the patient population. I think that's going to help us going forward. That's more in line with what Breyanzi and lisocabtagene maraleucel has done. Okay. Got it. So broader population that would be applicable for 314. Okay. And then in terms of, you know, we've heard some physicians say maybe they would, you know, treat with a CAR T in second line versus wait till third line. We had a discussion recently, and maybe you could help inform some of the investors about, you know, the opportunity in third line initially before you even get to second line. Yeah. Charlie, you want to start with that? Yeah. I would say I kind of walked you through the progression from first line to second line and what that patient population looks like. I think the data on progressors from second line to third line is a little bit more variable if you look across studies. I think the way I'd characterize it is the center of gravity, if you will, of most of the studies out there suggests that about 50% of patients that progress in the second line progress from second line to third line. While the third line setting is not as large of a patient population, obviously, that we'll be going after initially, it's still a significant patient population when you think about the number of patients that aren't responding today in that second line setting. Yeah. Some people say to me, well, you know, CAR T- cells or CD19 CARs are approved in the second line. Are there any third-line patients? If they're going to the CAR center, aren't they all getting it in the second line? The fact of the matter is, no, they're not, right? What happens is many of them are in the community when they progress on the first line. They take some time to get into a CAR T- cell center, right, and get signed up for CARs. They get started on that second line, oftentimes in the community before they're even referred in. By the time they get to the CAR T- cell therapy center and are ready, they're oftentimes in the third line already. We believe it's a little bit of a blurred line in between the second. Second is clearly the bigger market, but there are third-line patients for sure. We think it's going to be an important strategy to help us, again, get approval and to market quickly. Very helpful. Just to help clear that up for everyone to understand that there are multiple markets. It's not just one that, you know, people are second line is capturing and there's no third population. That's right. Okay. Great. And for second line, with the data that you all have generated recently, the first look at the data, could you just talk about, you know, how that relates to the approved CD19 CAR T therapies? Yeah. Again, I think the most important point that we've been able to show to date is this benefit in sort of the older primary refractory patients. And when we look very carefully, I think in many cases, as we talked about, Yescarta excluded those patients, right? Because in their second-line study, they didn't allow bridging therapy, which if you've got, you know, very difficult to treat disease, you can't wait for CAR T -cell therapy. These second-line patients, we get calls all the time. I've got a second-line patient. They're hot. They need their treatment soon. Get us a slot. Those patients need bridging therapy to hold for CAR T- cell therapy. If you excluded those from your trial and you only allowed light steroid treatment, that's a different patient population. Where we find, you know, sort of that older primary refractory patient population to sort of compare more apples to apples with is in the Breyanzi pilot study where they did allow older patients and they did allow, you know, bridging therapy. What we found was there in the pilot study, the primary refractory patients had a 46% complete response rate. Again, we're showing a 64% complete response rate. This sort of consistent benefit above and beyond the CD19s. When you ask again why, I think it gets back to the biology. We're targeting two antigens, right, that is driving these deeper.