All right. We'll go ahead and get started. Thank you all for attending, and good morning, still about 5 minutes away from afternoon. Welcome to the inaugural Citizens Life Sciences Conference, inaugural because it's here in Miami. It's my pleasure to introduce the next presenting company, Lyell Immunopharma. Presenting for the company is Lynn Seely. This is a very unique story. We actually initiated on the company on Monday. We have an outperform on the name. The data has been spectacular in our view. Lynn's gonna talk to us a little bit about that. We'll dig into some of the details there. I always like to start off our conversations.
I never know who's listening in the webcast, who's in the audience, who might or may not know the story. Can you just give us an overview in 2-4 minutes about, you know, the Lyell Immunopharma story?
Sure. I'd be delighted to, and thanks for having me in this beautiful spot. Lyell Immunopharma is a cell therapy company. We're focused on developing first-in-class, next-generation cell therapies, both for patients with hematologic malignancies, where CAR T-cell therapy is well-established, and also for patients with solid tumors. Lyell has 2 clinical programs, each focused on large, multibillion-dollar marketplaces. The first we have is a dual-targeting CD19/CD20 product we call Ronde-cel.
It's in development for patients with large B-cell lymphoma, and it was designed very specifically to bring more complete responses and longer duration of complete responses based upon its dual targeting mechanism, which is sort of obvious, and then also because it has a very special manufacturing process where we specifically enrich our product for patients with more fit, naive T cells that have more ability to persist and kills cancer cells for longer. That's Ronde-cel. It is in 2 pivotal trials as we speak, so we have a single-arm trial in the third- or later-line patients with large B-cell lymphoma that is well underway, and we'll be having a significant data update in the H2 of this year.
We have a first of its kind head-to-head CAR T-cell trial ongoing, which is Ronde-cel versus investigator's choice of either the approved products Yescarta or Breyanzi. This gives you some idea of just how confident we are in the performance of this product. There's more. We have our second clinical program, which is called Lyell 273, and this is a very novel CAR for patients with metastatic colorectal cancer. I think you all know that metastatic colorectal cancer is surging, particularly in young patients who would really appreciate a one-time treatment that could bring them some meaningful benefit. I think one of the problems with colorectal cancer is that they're really not good therapies for patients who progress after more than one or 2 lines of therapy.
We're in development in a phase I trial for patients with metastatic colorectal cancer in the third or later line. This is a really novel CAR design. It was invented in China. There's proof of concept data, clinical data in 15 patients from China where they saw 40% overall response rate and a median overall survival of 25 months, which really is better than anything that's been seen in approved products to date. This Chinese company brought the product to the U.S., and some premier medical centers have been participating in this phase I study. Lyell acquired the product at the end of last year and is continuing to develop it. We're seeing meaningful clinical activity with a manageable safety profile.
We believe this is a really transformative product for the company that will be having 2 data updates this year and really an opportunity to move rapidly, we hope, to pivotal trial.
Excellent. Let's dive right into it. The third-line plus setting in LBCL, this is the PiNACLE study. It's ongoing. You mentioned as in your overview that there's a significant data update in the H2 of this year, and at least according to our milestones, you know, there's the potential for the final data, you know, by the middle of next year. Can we talk a little bit about this trial design? I believe you mentioned it was single-armed. What kind of data, major data can we get, you know, in the H2 of this year? You know, I guess also this trial has been enrolling quite well. Can you tell us a little bit about the enrollment dynamics?
Sure. Just to set the stage, this is what we call our fast to approval strategy. It is a single arm study, and this is a really elegant design where the phase 1, 2 clinical trial can seamlessly expand into the pivotal trial. We've been enrolling patients in this trial for a while now. We presented data at ASH at the end of last year where we showed a 93% overall response rate and a 76% complete response rate with importantly a median progression-free survival of 18 months.
Just to talk about how that compares with the market leaders right now in the CD19 space for large B-cell lymphoma, the market leaders that we intend to displace, they have about a 70% overall response rate, a 50% complete response rate, and only a 6- to 7-month median progression-free survival. This represents really an opportunity to have a significant advantage. Our data all come with a very well-tolerated, manageable safety profile that patients have a cytokine release syndrome rate of 0 for grade 3 or higher. We've not seen any cases of grade 3 or higher cytokine release syndrome and less than 5% incidence of grade 3 or higher ICANS, which is a neurotoxicity syndrome. The efficacy and the safety in the third or later line has been looking really good.
As you say, we're gonna have a meaningful data update, which is more mature data with more patients in the H2 of this year because we're on our way to having the pivotal data set mid-next year with a BLA submission to follow. Why are we so excited about this? Because the primary endpoint of this trial is overall response rate. I just told you we have a 93% overall response rate. Even if there's some attrition over time with more patients, it's still well above the bar, which I just told you the CD19 CAR is set at about 70%. We're in very good position there.
We are even adding some new larger centers that are coming online in the Q1 of this year, and so that will even help us bring the trial to completion on track. We're really pleased with this. I think the one thing about the third or later line that a lot of people don't really appreciate is that it's potentially a much larger market than people think. We estimate it's about 6-7 thousand patients because a lot of times physicians intend to give CAR in the second line because that's what's recommended, and that's their intention. These patients are oftentimes diagnosed in the community, or they fail their frontline therapy in the community, and then they need to be referred into a CAR T-cell center.
It takes time to get their appointment and their apheresis chair. Many of these patients get a second regimen of chemotherapy before they receive CAR, and data in the literature suggests about 50% of patients. We think that this market in the third or later line is really meaningful, and we intend to be the first approved in the third or later line among the CD19/CD20s.
As you had mentioned longer follow-up in the H2 of this year, remind us how many patients worth of longer follow-up data will we see and you know, what should we be expecting? 'Cause you know, the median PFS is already there, right? You know, what are we seeing just longer spider plots? Like what is it that you really wanna highlight?
Sure. I think it's going to be we presented about 30 patients with a median duration of follow-up about 12 months in December last year. We're continuing to enroll, so we're gonna be having more patients with a longer duration of follow-up. We'll see if that median duration of progression-free survival of 18 months holds, if it gets longer, if it's a little bit shorter. I think mostly it's to give people confidence in the safety profile and the overall response rates that are gonna make up the BLA submission at the end of next year and the pivotal data set. We are very confident this product has behaved very consistently since inception.
It has a very reliable manufacturing process, so we're feeling very good about where we are with this program.
Let's switch gears to the earlier opportunity, the PiNACLE head-to-head study now in second line.
Mm-hmm.
You just started dosing patients, so congratulations on that.
Thank you.
It's a pretty ambitious trial, if you will, right? 400 patients, correct me if I'm wrong, head-to-head against CAR T. I don't think that's ever been done before. Why, you know, why do that? Tell us a little bit about, you know, what you expect from this study kinda based on prior data that you've had, and when do you think this study could potentially complete?
Yeah. A lot of questions in there. I'll do my best. I think the most important thing to know, if PiNACLE is our fast to approval or fast to market strategy, PiNACLE head-to-head is our leave no doubt strategy. We're obviously very confident in the performance of our product, and so we want to give patients and the physicians who treat them the very best data they need. It's very hard to do cross-trial comparisons in the CAR T-cell space with large B-cell lymphoma. Who you enroll, the patient disease characteristics and demographics really matter when you're interpreting outcomes. Running a head-to-head trial gives us an opportunity to randomize and stratify those patients. It's gonna be very even. You're not gonna have to look back and struggle with cross-trial comparisons. You're gonna be able to see in the data set.
We've already talked about in the third line how much better we're seeing above what's been presented to date from the CD19 CARs. This typically will read through to the second line already. In our second line data, we did have a single-arm cohort in our phase 1/2. We're showing really robust in the highest risk patient population. These are patients that are called primary refractory. They didn't even respond to frontline chemotherapy, and so they're the most difficult to treat. If you talk to lymphoma experts, and we had one lymphoma expert from MD Anderson who told us that when he sees these patients, he oftentimes initiates end-of-life conversations with them. These are very difficult to treat patients, and yet we were able to show a 61% complete response rate in these patients.
That it's hard to find the comparator number for the CD19 CARs in the second line because quite frankly, they don't report them out, and maybe there's a reason for that. But we did find that in the pilot study, which enrolls similar patient to ours, older patients, they did report out their primary refractory data, and it had a complete response rate of 42%. That's with Breyanzi, the market leader right now. We're feeling very confident about our second line data. We're going head-to-head, and I think physicians and patients are gonna know this is a superiority trial. You're right, it's 400 patients. It's sort of powered conservatively, for sure. We also have an interim analysis there, so we have an opportunity to get out early if the data are even better than expected.
We're very confident. We're not guiding yet about when the data will be out because as you know, we need some time. This has never been done before. We're the first, and so we wanna get a little bit better feel for how enrollment's going and how events are coming, and then we'll give some update on our progress in the H2 of this year.
As if LBCL and the data you've generated already wasn't surprising enough, right? You've actually improved upon the current standard of care. I think the one thing, you know, and I've been following the cell therapy space for a while. CAR Ts have been trying to get into solid tumors for a long, long time and, you know, unfortunately not so good results. This CRC data that you've reported is probably some of the best that I've seen. Not just from approved, call it third line plus CRC agents that are out there, which I think have objective response rates of less than 10%, but also from a PFS, you know, perspective. You did this deal at the end of last year.
Would love to kinda just hear, you know, how you're thinking about the CRC space. You've mentioned some of the data. We're getting 2 updates this year, the H1 update and a H2 update. What's the difference between the 2? Ultimately, what do you do with this? You know, once the data's done, how do you advance this forward?
Yeah. This metastatic colorectal cancer program is really important for Lyell because I think it has the potential to be transformative. We have great data, de-risked data in the large B-cell lymphoma space with Ronde-cel that's moving towards pivotal trial. The holy grail of CAR T-cell therapy, as you say, is solid tumors, and this is something that Lyell has been focused on since inception. We've learned a lot, and we know a couple of things that the first thing we know is that you must have a great target. The target for this colorectal program that we acquired in the last year is a really great target. It's known as GCC for guanylyl cyclase C. It is expressed highly on the vast majority of colorectal cancers, over 95%. We don't need a biomarker for this program, and it's not spotty across the tumors.
It's very homogeneously expressed. This is what a great target looks like. We know we need more than just a great target. We need something to help the cells expand well in the solid tumor space because if they don't expand, they can't infiltrate into tumors. We need good expansion, which has been a problem in the past. The other thing, of course, that's a problem is the very cold, hostile immunosuppressive tumor microenvironment. It makes it very difficult once the cells infiltrate to actually continue to kill cells. Well, this product really has overcome those barriers with a very novel design, and it's active in patients. We have 15 patients from China that have been published in JAMA Oncology that show a very active agent, including in patients with liver metastases. These aren't the best of the best fittest patients.
These are patients that have liver metastases, which in some cases have resolved with this CAR. We have patients that had 15 patients from China that had a median overall survival of 25 months. When you look at approved therapies in the U.S. for third or later line metastatic colorectal cancer, the median overall survivals are 6 months or less. This appears to be an active agent. This company, as I said, brought it to the U.S. The premier medical centers are participating in this trial, University of California, San Francisco, Dana-Farber, City of Hope, University of Colorado, and you know, are seeing and confirming those data, a clinically active CAR with a manageable safety profile. What are the data updates coming?
When I talk about the safety profile, with any target, you're always looking for, are there any side effects that come from this? Diarrhea has been a side effect from this CAR. It's highly expressed on colorectal cancers. It's expressed at low levels in the normal bowel. So there has been one patient that had problems with some significant diarrhea and some consequences from that. He got treated with immunosuppressive therapy and ended up unfortunately getting a sepsis, a fungal sepsis, and died. The diarrhea was controlled, but the infection that followed was a problem. That patient died with no evidence of disease, despite having widely metastatic disease.
It's an active agent, so what we're gonna be reporting on is more safety data in the H1 with a real focus on additional patients treated, and what that safety profile is looking like. We have said that we've already dosed an additional 7 patients and escalated to dose level 3. We've currently been treating at dose level 2 and haven't seen any further dose-limiting toxicities. More detailed safety data will be coming, and in the back half of the year, we'll be providing more outcomes data. I think this is really important, right? Because this program, we expect to go quite quickly. We are targeting an end of Phase 1 meeting by the end of the year and expect to be in pivotal trials by the H1 next year.
The unmet need in this space is tremendous, and when you see the surging incidence in young people, I mean, these are people who are perfect for CAR T-cell therapy, right? Because they want one and done treatment, get back to their normal lives without ongoing chemotherapy. They're working, they have children. This is a huge problem. We're very excited about this program, and I think we're continuing to execute and look forward to getting out more data.
The uniqueness about this CAR, I think you had mentioned it's a different design. This is one of your armored CARs. Is that correct? Can you just remind us what that is?
Yeah. This was a product I have to give credit to the innovators. It's a company called Innovative Cellular Therapeutics that we licensed this from. What the inventor did, picked a great target, GCC, but then actually partnered it with CD19 CAR. You say, "Well, CD19 CAR, that's unusual. That's a heme target." In fact, what these CD19 CARs do, they're not just CD19 CARs. They're engineered to release cytokines upon activation. When you infuse these CAR T-cells into patients, they hit B-cells. Cytokines are released because the CD19 gets activated, and the cytokines help with the overall cell expansion. We get really nice cell expansion of the GCC-targeted CARs and some doublet cells that have both GCC and CD19.
These then infiltrate into the tumor, continue to release cytokines, which help flip the tumor microenvironment, warm it up, attract more immune cells into the tumor, and suddenly you're starting to see this activity and cell killing in solid tumors. We believe this is not only important for therapy to work in solid tumor more largely. The other thing we really like about this CAR is GCC is expressed on the majority of more than 50% of pancreatic cancers as well. This has potential in late-line colorectal cancer. If the data continue to look good, it can move earlier and then of course to pancreatic cancer. We're very bullish on the novel mechanism on the target, but most importantly on the fact that it's a clinically active CAR.
Before we go to manufacturing, which I know is a big deal in the cell therapy space.
Mm-hmm.
In terms of the registrational study, is this?
Whether it's gonna be a response rate, single arm study, or a randomized controlled trial, that will come later after we have our interaction. I think this will go quickly because there's so much unmet need here.
In the last 4 minutes we have left, let's tackle manufacturing 'cause that is a big deal in the space. You know, what's the vein to vein time here with both your products Ronde-cel and LYL273. And then, you know, maybe just a little bit about your in-house capabilities.
Yeah. Manufacturing is always of supreme importance in CAR T-cell therapy, and Lyell invested very early on in its own manufacturing center. State-of-the-art, it's digital. It is capable of commercial launch. We've got the infrastructure that we need. We'll add some headcount, but we have our facility that will help us launch commercially. Currently for Ronde-cel, we have a semi-automated manufacturing process. It's relatively low touch. It's very simple and straightforward and reliable and robust. We have a vein-to-site time we call vein-to-site time because once it gets to the site, sometimes they get delayed for various reasons. But a vein-to-site time, a median of 16 days, that's highly competitive with the best, which is Kite Gilead, maybe around 14 days.
BMS is longer, so we're very competitive from that standpoint, and we have a greater than 95% success rate. I feel like we're very strong. The GCC CAR LYL273 has actually even a more automated manufacturing process. We're in the process of transferring that to our Lyell facility now. It is a very straightforward manufacturing process, quite standard and takes relatively about the same time.
Okay. You have your own manufacturing plant. You have 2 pivotal studies that are ongoing. Potential for a third by next year. Clearly, you need finances to fund all this. Give us an update on your latest kinda financial position. How long do you think it lasts?
Yes. Well, we just announced on Monday that we have taken the second tranche of a $100 million PIPE that we did in July. We did the first $50 million tranche at the time of doing that at a 30% premium to the price at the time, which was $10. We just took the second tranche after hitting a clinical milestone in our Ronde-cel PiNACLE trial. That was at a 150% premium or a price of $25.61. That helps. We do have cash well into Q2 and getting us well along our path.
Yeah. I think we probably quickly did the math. I think between the payment that you had to ICT, is that right? In the Q4 and this $50 million that came in, you're probably around 320. Did I-
We haven't put out our 10-K.
Okay.
Yes, if you do the math, we had about $320 at the end of the last quarter, and we did have this outflow to ICT, so.
Got it. In the last, you know, minute or so that we have, I guess one, your thoughts on the competitive landscape. 'Cause clearly Kite, Gilead, right, BMS is not. They're not just going to give this to you. They're gonna keep fighting. They're established. Outside of that clinical data, are you noticing dynamics in the space that suggest that, hey, even if you're a third entry or a second entry, you can still, you know, change the market around based on the profile you have?
Yeah. We are the first in class. This is a CD19/CD20. We're clearly in the lead. We're outperforming our competition that we've got 2 pivotal trials ongoing, and I think this is known to be a switching marketplace. If you look at Yescarta, which is the Kite-Gilead product, they were first to market, and then Breyanzi is now the market leader because they bring most likely a better safety profile, and switching is occurring. These CAR T-cell prescribers are switchers. They're very data-driven. If you bring better safety or efficacy, in our case we intend to bring both, they will switch. You've seen that Abecma got taken out by Carvykti, and we like to say we are the Arcellx of lymphoma because in multiple myeloma, Arcellx is now planning to get the field to switch from Carvykti to Arcellx.
This is a switching marketplace, and Lyell intends to bring better, first-in-class safety and efficacy data.
The last 5, 10 seconds, we talked about different milestones kinda sprinkled throughout our conversation.
Mm.
Just to end it with a concise note, what are the next several milestones or the next-
The time to pay attention to Lyell is now. We're gonna have a data update in the H1 of our colorectal program, a data update in the H2 in our colorectal program, and then a big data in the H2 on PiNACLE. This is a big year for Lyell, and I think now is the time to pay attention. It's a new story, and it's a rapidly evolving story.
Excellent. Lynn, thank you very much. Appreciate it.
Thank you.