Lyell Immunopharma, Inc. (LYEL) Earnings Call Transcript

All right. So we'll go ahead and get started. Thank you all for attending, and good morning, still about 5 minutes away from afternoon. But welcome to the inaugural Citizens Life Science Conference, inaugural because it's here in Miami. And it's my pleasure to introduce the next presenting company, Lyell Immunotherapeutics and so Immunopharma. Presenting for the company is Lynn Seely. So 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. And so Lynn is going to talk to us a little bit about that. We'll dig into some of the details there. But I always like to start off our conversations. I never know who's listening on the webcast, who's in the audience who might or may not know the story. Can you just give us an overview in 2 to 4 minutes about the Lyell Immunopharma story?

Sure. I'd be delighted to, and thanks for having me in this beautiful spot. So 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 kill cancer cells for longer. So 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 second half of this year. And then 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. And this gives you some idea of just how confident we are in the performance of this product. And then there's more. We have our second clinical program, which is called LYL273, and this is a very novel CAR for patients with metastatic colorectal cancer. And I think you all know that metastatic colorectal cancer is surging, particularly in young patients who would really appreciate a onetime treatment that could bring them some meaningful benefit. I think one of the problems with colorectal cancer is that there are really not good therapies for patients who progress after more than 1 or 2 lines of therapy. And so 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. And we're seeing meaningful clinical activity with a manageable safety profile. So we believe this is a really transformative product for the company that we'll be having 2 data updates this year and really an opportunity to move rapidly, we hope to pivotal trial.

Excellent. So let's dive right into it. The third line plus setting in LBCL. This is the PiNACLE study. It's ongoing. You mentioned in your overview that there's a significant data update in the second half of this year. And at least according to our milestones, there's the potential for the final data by the middle of next year. And so can we talk a little bit about this trial design? I believe you mentioned it was single arm. What kind of data -- major data can we get in the second half of this year? And then I guess, also, this trial has been enrolling quite well. Can you tell us a little bit about the enrollment dynamics?

Sure. So 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 I/II clinical trial can seamlessly expand into the pivotal trial. So 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. And 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. So this represents really an opportunity to have a significant advantage. And our data all come with a very well-tolerated and 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. So the efficacy and the safety in the third or later line has been looking really good. So as you say, we're going to have a meaningful data update, which is more mature data with more patients in the second half of this year because we're on our way to having the pivotal data set mid next year with a BLA submission to follow. And so why are we so excited about this? Because the primary endpoint of this trial is overall response rate. And I just told you, we have a 93% overall response rate. So 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%. So we're in a very good position there. We are even adding some new larger centers that are coming online in the first quarter of this year. And so that will even help us bring the trial to completion on track. So we're really pleased with this. And 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 6,000 to 7,000 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. But 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 here. And so many of these patients get a second regimen of chemotherapy before they receive CAR, and data in the literature suggests about 50% of patients. So 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 CD19/20s.

And so as you had mentioned longer follow-up in the second half of this year. Remind us how many patients worth of longer follow-up data will we see? And what should we be expecting? Because the median PFS is already there, right? Is what -- are we seeing just longer spider plots? Like what is it that you really want to highlight?

Sure. So I think it's going to be -- we presented about 30 patients with a median duration of follow-up of about 12 months in December last year. So we're going to -- we're continuing to enroll. So we're going to be having more patients with a longer duration of follow-up. And so 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. But I think mostly, it's to give people confidence in the safety profile and the overall response rates that are going to make up the BLA submission at the end of next year in the pivotal data set. So 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.

So let's switch gears to the earlier opportunity, the PiNACLE head-to-head study now in second line. You just started dosing patients. So congratulations on that. 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 do that? And tell us a little bit about what you expect from this study kind of based on prior data that you've had? And when do you think this study could potentially complete?

So a lot of questions in there. I'll do my best. So I think the most important thing to know is 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. And 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. And so running a head-to-head trial gives us an opportunity to randomize and stratify those patients. So it's going to be very even. You're not going to have to look back and struggle with cross-trial comparisons. You're going to be able to see in the data set. And we've already talked about in the third line how much better we're seeing above what's been presented to date in the -- from the CD19 CARs. And 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 I/II. We're showing really robust in the highest risk patient population. These are patients that are called their 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. And 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 enrolled similar patients to ours, older patients, they did report out their primary refractory data and it had a complete response rate of 42%. So that's with Breyanzi, the market leader right now. So we're feeling very confident about our second-line data. We're going head-to-head. And I think physicians and patients are going to know this is a superiority trial. You're right. It's 400 patients. It's sort of powered conservatively for sure. But we also have an interim analysis there. So we have an opportunity to get out early if the data are even better than expected. So 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 want to get a little bit better feel for how enrollment is going and how events are coming, and then we'll give some update on our progress in the second half of this year.

So as if LBCL and the data you've generated already wasn't surprising enough, right? So you've actually improved upon the current standard of care. I think the one thing -- 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 with unfortunately, not so good results. This CRC data that you've reported is probably some of the best that I've seen. And so 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 perspective. You did this deal at the end of last year. I would love to kind of just hear how you're thinking about the CRC space. You've mentioned some of the data. We're getting 2 updates this year. The first half update and the second half update, what's the difference between the 2? And ultimately, what do you do with this -- once the data is done, how do you advance this forward?

Yes. So this metastatic colorectal cancer program is really important for Lyell because I think it has the potential to be transformative. We have great data derisked data in the large B-cell lymphoma space with ronde-cel. That's moving towards pivotal trial. But 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. And 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. So this is what a great target looks like. But 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. So 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. So these aren't the best of the best for the 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 later-line metastatic colorectal cancer, the median overall survivals are 6 months or less. So this appears to be an active agent. This company, as I said, brought it to the U.S. Premier medical centers are participating in this trial, University of California, San Francisco; Dana-Farber; City of Hope; University of Colorado and are seeing and confirming those data, a clinically active CAR with a manageable safety profile. So 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. And diarrhea has been a side effect from this CAR. It's highly expressed on colorectal cancers. It's expressed at low levels and the normal bowel. So there has been 1 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 going to be reporting on is more safety data in the first half 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. So -- but more detailed safety data will be coming. And in the back half of the year, we'll be providing more outcomes data. And I think this is really important, right, because this program, we expect to go quite quickly. We are targeting an end of Phase I meeting by the end of the year and expect to be in pivotal trials by the first half next year. The unmet need in this space is tremendous. And when you see the surging incidents 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. They have -- this is a huge problem. So 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? And can you just remind us what that is?

Yes. So this was a product. I have to give credit to the innovators who is a company called Innovative Cellular Therapeutics that we licensed this from. But what the inventor did picked a great target, GCC, but then actually partnered it with CD19 CAR. And you say, well, CD19 CAR, that's unusual. That's a heme target. But in fact, what the CD19 CARs do, they're not just CD19 CARs, they're engineered to release cytokines upon activation. And so 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. And so 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. And so we believe this is not only important for colorectal cancer in this product, but it's actually a window on how to get cell therapy to work in solid tumor more largely. And 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. So 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. So 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 our -- in the cell therapy space, in terms of the registrational study, is this something that would likely be a single-arm study and less than 100 patients? Or is it something more? Do you need to wait to tell?