Hello everyone. My name is Nitshul Kapoor. I'm a Senior Biotech Analyst at HC Wainwright. It is my pleasure to welcome the Lyell Immunopharma team for a fireside chat. Today we have Lynn Seely, MD, the CEO, and Charles Newton, the CFO. Thank you so much, Lynn and Charles, for joining us.
Thanks for having us. It's great to be here.
Great. Maybe you could kick us off with a brief overview about Lyell and the key initiatives today. Where are you at with the company in the pipeline?
Sure. Lyell Immunopharma is a clinical stage oncology company focusing on bringing next-generation cell therapy to patients with cancer, both with hematologic malignancies as well as with solid tumors. Our lead program is a dual-targeting CD19/20 CAR T cell therapy for patients with relapsed and refractory aggressive large B-cell lymphoma. We are very excited about this program. We have put out some very promising data, and we have a pivotal single-arm study underway for approval in the third-line setting. We also just announced we are launching a second-line phase 3 randomized head-to-head trial in this space. There is a lot going on at Lyell. We are continuing to work on solid tumors in the background, and we will be bringing a fully armed CAR forward next year. There is a lot happening. We are very excited about it and look forward to telling you about it in more detail.
Great. Wonderful overview. Just jumping into RondaCell, could you talk about how it's a disruptor to the entrenched CD19 CAR T cell therapies? At a high level, what's the single most important data point or strategic move that should give investors conviction that the program can reset the LBCL paradigm?
Sure. First, we just announced that we have our generic name. We're no longer calling it LYL314. It's now called RondaCell. We're very excited about that. I think with RondaCell, it really is a step forward. It's a dual-targeting CD19/20 CAR. What we're seeing is data, which is really a cut above what you see with the CD19 CARs. It makes sense because we're targeting two different antigens. Sometimes malignant B cells that cause lymphoma will express a lot of CD19, so the CD19 CAR will work with them. Oftentimes, there may be low CD19, and that's where a CD19/20 can really kill more cells and bring deeper, more complete responses. We recently showed that with our CD19/CD20 CAR, we had an 88% overall response rate and a 70% complete response rate in patients with relapsed disease in the third or later line setting.
This corresponds to, with the currently approved CD19 CARs, an overall response rate of 70% and a complete response rate of 50%. It's really a marked step up in response rates. We think that's really what patients are looking for, is they're hoping to get into remission and stay in remission, this disease-free, treatment-free period for as long as possible.
Wonderful. Okay, great. When we speak with investors, a lot of interest around this asset and a lot of interest in the space and the CD19/CD20 CAR Ts in general. A lot of investors are wondering how we can compare across, and there's always limitations in cross-trial comparisons. One of the things that has come up repeatedly is the proportion of patients who are treated and then stay in a complete response for six months or longer. A lot of folks in trials reported differently about complete responses persist, complete response rate, PFS, et cetera. I guess how would we benchmark against Yescarta, Breyanzi, Kite363, and J&J's somewhat immature asset as well to understand a little bit more about how you guys sit in the landscape?
Yeah, it's a great question. It's a complicated question. Maybe let me lay out the playing field a little bit. I think what's really changed even in just the last six months is it's become very clear to the field that the CD19/CD20s, these dual-targeting CARs, are really putting out data above and beyond what the CD19 CARs have done. Lyell Immunopharma has a very nice data set, as you alluded to. There are others, Kite, Gilead, and J&J, and consistently the benefit across those programs looks stronger than with the CD19 CARs. I think that's really something that has changed and is quite remarkable in the field. We can just look at complete response rates and overall response rates because they're so much higher with the CD19/20s than with, for example, Yescarta and Breyanzi.
Now, response rates are important, but as you point out, the duration of that complete response, the duration that the patient can really stay in remission, is also important. What we're looking for is as long a duration as we can find. With Yescarta, for example, that's probably one of the better known, it's a leading selling product right now. The complete response rate at six months is about 40%. That's sort of the bar to beat in the third or later line. That's really what we're targeting. What we've been able to show is not only do we have a 70% complete response rate when they have a 50% complete response rate out of the gates, we have 71% of our patients who achieve complete response or incomplete response at six months. We're really pleased with those data.
Great. As we think about the bar as it compares from third line to second line, and we think about the number of patients who come onto therapy versus the patients who remain in a six-month complete response (CR), what kind of bar should investors set so that they can look across the landscape and say, you know, this is the best in second line, this is the best in third line? What is that bar?
Yeah. It gets complicated, as all things, when you're looking at data sets. Certainly, as you said, doing cross-trial comparisons is difficult because patient populations differ. Particularly in the second line, one of the things when we presented our second-line data at the big lymphoma meetings this past June, we were able to show in our particular patient population, 91% in the efficacy evaluable set had primary refractory disease. That's a very hard and difficult disease to treat. If you look at Breyanzi, as its brand name, they have, if you look at their transplant-eligible patients, about a 66% overall response rate or complete response rate. If you look at their primary refractory patients, it's much lower, 46%. Age matters also. They have two trials. One is transplant-eligible patients. One is transplant-ineligible patients that are older and that have oftentimes more significant comorbidities and disease. The outcomes are different.
You have to look at the patient population, the risk factors. In our trial, we've been very transparent about that. You can see not only the response rates, the duration of response, but also assess how sick the patients are. I think that matters a lot. You see that consistently across trials. We think that what we're looking for is good response rates, even in the harder-to-treat patients, as well as duration of response.
Wonderful. The entrenched CAR T cell therapies have long-term data now because they've been on the market for a while. In ZumaOne, the five-year follow-up was 43% of Yescarta patients remain alive, 92% of those receiving no additional treatment. This is deep, durable remission for some patients. At what point, since that's so far away, at what point can we definitively say that RondaCell is showing definitive evidence that you all are stripping away from that type of a profile?
Yeah. Obviously, it's going to take us some time to get that sort of long overall survival data. I think what speaks loudly here is the biology, right? We understand how this is working and that CD19 and CD20, two targets, is better to bring deeper complete responses. Also, malignant B cells can drop antigens over time, become resistant to therapy. It's much harder to drop two antigens than it is just one. We think that's going to give us an advantage in duration of response, even in the sicker patients, as we were discussing. I think this is going to be emerging. People are going to be looking at complete responses as well as duration of response. There will be people who say, oh, we can't use a new treatment until we have overall survival.
There are going to be a lot more people who are going to say, look, we know in late-stage lymphoma that complete response rates and duration of response have correlated very nicely with overall survival. This clearly looks better. Again, remember, it's not just our data set. It's others in the field who are bringing CD19/20s that also look better. These confirm one another and give us great confidence. I mean, we are moving forward with a head-to-head trial because we are so confident. In that trial, any differences in patient populations are going to wash away, right? It's going to be randomized. This gives us a tremendous advantage to ask and answer that question and leave no doubt in the superiority of our CD19/20 RondaCell.
Excellent. With the focus being on the competitive landscape, besides data and what we've seen, can you compare across Kite and J&J and what the differences are between kind of the constructs? Is it the biology, the safety, the manufacturing, things that will drive differentiation between the different programs?
Yeah. There are some similarities, some differences. Let me describe the others first, then I'll say how ours stands apart. The Kite/Gilead product is really two CARs, one CD19 CAR and one CD20 CAR. The CD19 CAR is Yescarta, and then they have a CD20 CAR. Both J&J and Lyell have a single tandem CAR, so it's one CAR that has binding sites for both CD19 and CD20. Ours is a true orgated CAR, so it's full potency at CD19 and it's full potency at CD20, but it's in just one CAR construct. It's a 4-1BB CAR, and that's important because 4-1BB CARs are associated with less neurotoxicity than, for example, Yescarta has. All three companies are studying these. They have put up data. Our program is very similar to J&J's. In fact, we think we have dominant patent position and that their construct is very, very similar to ours.
What we have, which is unique, is we're the only company that is selecting and enriching our cell product for naïve central memory T cells. We have a very naïve T cell product, which is known to be associated with better outcomes in overall survival, better persistence, and engraftment. We think that is a competitive advantage that only we have. Everybody's going to be putting up data. We're going to try and compare and contrast based upon the patient populations. Right now, we think we're in a leadership position. We're the first to be in two pivotal trials. We're the first to announce a head-to-head trial. On the safety front, it's really interesting if you look carefully at the safety data that we really look to have the gentler product.
I say that because if you look at overall rates of CRS, for example, they're much higher in the Kite/Gilead and even the J&J product in the 80% range versus ours is 47% or 57%. They use much more tocilizumab, and 80% of patients or 90% of patients in Kite/Gilead got tocilizumab, which is what you use to treat CRS. Only 40% of our patients got it, so it tells you there's some difference. When you look at ICANS, 46% of patients on the Kite/Gilead product got ICANS, which is that neurotoxicity side effect that we really want to avoid, versus only 22% with our treatment. Since then, we've instituted some prophylactic treatment to prevent the neurotoxicity with good result.
Great. I think one point that folks might be overlooking is the fact that in the current market, there are multiple CAR T cell therapies. I would love to hear your thoughts on if all are successful in this new class of CD19/CD20, which are looking all promising versus the current therapies, how does the market shape out? Is this the birth of a new class in a sense?
Charles, you want to get you in the conversation? You want to take that?
Yeah, look, I think that given the success that we have seen and that J&J and Gilead have seen from an efficacy standpoint relative to the existing CD19s, that if we're all successful, and certainly we feel very confident with our product profile and potentially being not only a best in class but potentially first in class as well, that we can really disrupt that market. As we've seen both in the existing CD19s today as well as in other CAR therapies like the BCMAs, if another product comes along with either better safety or even better, better efficacy, that product has been able to steal share very, very quickly and be able to maintain that share. We feel confident that we, and certainly the class as a whole, CD19/20, will be able to replace the CD19s.
That's why we've designed our pivotal study as a head-to-head study in the second line to really demonstrate that we have a better product and that that'll arm us to be able to capture significant market share upon launch.
Wonderful. Okay, great. Jumping back into the trial designs, can you describe the pivotal must-hit thresholds in the third line? Is it CR %, six-month CR, durability, safety? What do you think are those thresholds for those metrics?
Yeah, so we have two pivotal trials going. We're going to talk about the third-line first, as that's what you're asking about. That is a single-arm study. It's a seamless expansion of the phase one/two that we've already been reporting out. We're just continuing to enroll in that cohort of patients. We have had our end-of-phase one meeting with the FDA. We've aligned on what it will take to get this approved. It is a single-arm study for full approval, assuming that we hit the benchmarks. What I think a lot of people don't really appreciate is that the standard of care in the eyes of the agencies is sort of what's out there and approved and what's being used, chemoimmunotherapy, for example, as well as the CD19 CARs. The benchmark is not just the 70% overall response rate that the CD19 CARs have.
It's even lower than that because it's mixed with the chemoimmunotherapy as well. If we can maintain the overall response rate or get close to it that we've already put up of 88%, we should beat that bar in a nice way. Overall response rate is the primary endpoint. The agency does look at duration of response, and we're required to follow all patients from the time of their first response for six months. What they're looking for is that overall response rate, and they just want to make sure it doesn't come and go very rapidly. I think it sets us up in an excellent way for approval. Back to your earlier comments, of course, people are going to want to see a nice duration of response.
That six-month CR rate as well will be informative as physicians try to decide, you know, are they going to switch and use this for their patients? When you look at the combination of efficacy, we know efficacy drives switching, but the combination of efficacy plus a nice safety profile like we're seeing, which we expect to be as good as Breyanzi, if not better, and better than Yescarta from a neurotoxicity standpoint, it really puts us in a strong position. The data will declare itself. We're going to have to see it mature. As I said, from a safety standpoint, we have instituted low-dose dexamethasone, so 10 milligrams of dexamethasone for three days at the time of infusion, and that's been shown to reduce toxicities like CRS and ICANS. We're seeing good results with that.
Great. Okay. In the second line, you've got it to a randomized controlled trial expected there. What competitors would you expect to be most likely? Would it be chemoimmunotherapy, CD19 CAR Ts, both? What label ambition drives that design choice? I guess would patients also be eligible for kind of a crossover to see how they might perform if they got one of the others?
We're really excited about this bold head-to-head trial because we are confident in the benefit and our ability to be able to show superiority. We're studying RondaCell, which is our, you used to call LYL314, versus the two most commonly approved CD19 CARs. The investigator can choose either Axicabtagene Ciloleucel, which is Yescarta, or Lisocabtagene Maraleucel, which is Breyanzi. They have to be used on label. What's really interesting about the RondaCell arm is we are taking a very broad patient population. We don't have an upper age limit. Remember, some of the earlier studies, if you were older than 75, you couldn't be in the study. We're successfully treating people into their 80s. We're taking patients who are really eligible for CAR. They can be early relapse patients. They can be relapse patients. A nice broad patient population. We'll be stacking up against the current approved CD19 CARs.
The primary endpoint is event-free survival. That's largely driven by progression.
Okay, great. You've mentioned that third line is a path to market, not just second line. Second line would obviously represent a bigger prize. Should you think about third line as a near-term commercial opportunity or primarily as a regulatory bridge? How do you think about what that opportunity means to be in third line while you're still pursuing second line?
Yeah. Do you want to take that, Charles?
Yeah, look, we think that the market opportunity in third line and second line, obviously, is a much larger market opportunity, but there's a significant market opportunity still in the third line setting for us to be able to tap into. As we launch in the third line and continue to have the data mature in the second line study and have that disclosed after the approval of the third line, that can only help with the stronger data set that we're able to share with clinicians.
Okay.
One of the things I should point out that we're doing, and I think, again, is very strategic, is that you might imagine your clinical trial sites are your initial commercial sites, right? They're the ones who are most familiar with the product and have been using it. We are very strategically setting up our clinical trial sites to include not only major academic centers, but also the large prescribing community, hospitals that can run high-quality clinical trials. It gives us a really nice footprint between the third line study and the second line study. When the third line launches, there are lots of sites that are going to be very familiar with our product.
Great. Okay. Moving to business development, is that something that's on your minds in terms of thinking about how you get a therapy like this to as many patients as possible? Is this a do-it-yourself kind of thing, or do you think you need a partner to try to push this commercially?
Yeah, we think it's entirely doable on our own to be able to develop this product and commercialize it and launch it on our own. That being said, we're always open to potential strategic options going forward. We're going to be very thoughtful about how we seek to maximize the size of the pie and our ability to create value for shareholders as we get closer to commercialization. As Lynn indicated earlier, with our manufacturing facility, we can do up to 1,200 doses per year. That gives us plenty of firepower to be able to launch the product on our own. That's a pretty meaningful piece of the overall market today.
If you look at the number of doses of Breyanzi and Yescarta in the U.S., our ability to be able to not only prosecute the clinical trials, but importantly, launch out of our Lyell facility gives us a lot of flexibility to do that on our own. From a strategic perspective, I'm sure that there are parties out there that have existing CD19 franchises that view our product as a threat. That could be an opportunity for us to think about potential collaborations, partnerships in the future. As we think about ex-U.S. opportunities, that's an obvious area that we might think about doing a partnership. We don't feel any sense of urgency to do that in the near term, just given the capital that we have today, the manufacturing footprint that we have today, and the ability to be able to execute on our own.
Wonderful. Finally, I want to look out 12 to 18 months from now. Can you help investors understand what one or two readouts will be the most significant in determining whether RondaCell is the next standard of care in LBCL?
I think very clearly it's going to be watching these data mature. We have these two cohorts where we're going to be providing a nice data update at the end of the year, really focused on the second line. You remember in June at the big lymphoma meetings, we presented a nice data set of third line, but the second line was sort of a sneak peek in early data log. Now we're going to have much more mature data with more patients. We'll be updating both on the third line as well as the second line by the end of the year. Of course, more data is coming about six months after that. I think you're going to continue to see data flowing out of these trials and then execution and progress on the clinical trials.
As Charles alluded to, we expect to have data from the third line trial in 2027.
Excellent. Thank you so much, Lynn. Thank you, Charles. Really appreciate your time today. Thank you to all of the investors that have joined today and dialed in.
Thank you.
Have a great day.