Lyell Immunopharma, Inc. (LYEL) September 2026 Conference Transcript

Great. Thank you all for taking the time to join us for another session at the Baird Healthcare Conference today. My name is Jack Allen, for those who I haven't met in the audience, and I cover the biotech space. And for this session, I'm joined by the CEO of Lyle Therapeutics, Lynn Seeley. Lynn, thank you so much for taking the time to join us.

I didn't have a chance to tell you about Lyle Immunopharma. For those of you who are not as familiar with Lyle, we are a cell therapy company focused on next year.

Okay. Thank you. Well, thank you again for taking the time to join us.

Well, thank you. I'm delighted to have a chance to tell you about Lyle Immunopharma. For those of you who are not as familiar, Lyle is a cell therapy company focused on next generation CAR T cell therapies for patients with cancer, specifically hematologic malignancies, as well as solid tumors. We have two programs in the clinic. Our lead program is RONDACEL, which is a next-generation CD19, CD20 CAR T-cell therapy in two pivotal trials for large B-cell lymphoma. We have a single-arm study, the PENICLE study, which is going to have a significant data update this year, and we expect our first BLA submission next year, so Lyle is on its way to hopefully becoming a commercial company. We also have a first-of-its-kind head-to-head CAR T-cell therapy company of our product, Rondocel, versus investigators' choice of one of the approved CD19 CARs, Axacel, or Lysacel. And then we have a second program in the clinic we call Lyle 273, which is a GCC-targeted CAR T-cell therapy for patients with metastatic colorectal cancer. So it's a full lineup, and I'm pleased to report we also have our own manufacturing facility, which gives us a lot of control over our destiny because that's a very important component of cell therapy.

Great. Thanks so much for the overview. I know we've got a lot of ground to cover today, but maybe we can start with Rondecel and step back and take a 50,000-foot view of Rondecel and the design of the product. So this is a CD19, CD20, or gated CAR-T. What does that really mean? Does it mean you can hit either antigen? And how does hitting both antigens change the safety and efficacy profile as compared to CD19 autologous CAR T's?

Sure. So just to back up a little bit, I think many people are aware that CD19 CARs have really transformed the treatment for patients with large B-cell lymphoma, which was really a very deadly disease in the past, and they've made great benefit. But what became quite apparent is there's still significant room to improve upon outcomes. particularly driving more patients to complete remission or complete response, as well as driving longer duration of response, because what patients are really looking for is this treatment-free, disease-free interval. And the beautiful thing about CAR T-cell therapy is it's a one-time treatment, which really is designed to bring those sorts of meaningful responses. And so the inventor of Rhonda Cell is an engineer-turned-biologist, a really brilliant scientist, Devon Chen at UCLA who really rationally designed this CAR T-cell therapy. And what she did is she wanted to design a CAR that was full potency at either CD19 or CD20. And this is really important because some malignant B-cells have no CD19, and so therefore CD19 CAR T-cell therapy won't benefit the patients at all. In this case, if the patient has either CD19 or CD20, we can benefit them, and that's expected to drive more complete responses. In addition, we know that one of the main causes of escape from CD19 cars is that the malignant B cells can drop the CD19 antigen itself as sort of this evolution to avoid therapy. Well, it's very difficult for these malignant B cells to drop two antigens. And so by having a dual-targeted car, we can drive more complete responses and longer duration of responses. But then she did one more thing, which was really quite special, is the field has really learned that if your CAR T-cell therapy product includes naive or central memory T-cells, these are the, think of as the more fit and healthy younger T-cells, that actually those are the cells that are associated with longer overall survival. For example, in the Zuma trials of AxoCell. And so we, she really designed this product to specifically have a high percentage of naive T-cells. So we think it's this combination of the dual targeting plus this very novel manufacturing process that is helping with the benefits that we're seeing.

Yeah, and to that end, the manufacturing process, while it does select, I believe CD62 is the marker that you select for, it's in line with CD19 autologous manufacturing process as it relates to timing from vein to vein. How do you think about that?

We just in early summer presented data where we on the first 100 patients that we've treated, we had a 97% success rate in delivering product to patient, and the median vein-to-sight time is 16 days, so very much in line with AxoCell and better than what Lysacell or Brianzi brings.

Yeah, it seems like it could be a real innovation as it relates to autologous CAR-T, where you already have these CD19s, but you could displace them with this dual antigen approach. You touched on the safety and efficacy profile, but maybe could you dive a little bit more deeply into what you've seen so far in the clinical results with Rondacel, and what has you excited about the two ongoing pivotal studies?

So very much so. So this product was designed with a specific outcome and intent. And in fact, that's exactly what we're seeing in the data. We're seeing this in translational data that we presented at ASH last year, really showing very nice cell expansion, long persistence and duration of response. But most importantly, when we presented data at ASH last year, we had a 76% complete response rate in patients with third or later line disease, patients who have been failed by two prior lines of chemotherapy. That's important because if you look at the CD19 CARS, they have in that line of therapy about a 50% complete response rate, so a substantial improvement. And then what really got us a lot of attention is the median progression-free survival that we presented last year was 18 months. And that, again, compares very favorably with what has been presented for the CD19 CARS, which is six to seven months of median progression-free survival. So again, it's pulling through this longer duration of response and more complete responses.

And then maybe very briefly on the safety side of things, too. I think you've seen an improvement on the tolerability profile by hitting the dual antigen approach.

Yes, and maybe also because of the CD62L selection. We're seeing almost what we call a softer, I should say the investigators have told us, is a softer safety profile. We've had no grade 3 or higher CRS cytokine release syndrome, which is a classic CAR T-cell associated adverse event. And then neurotoxicity or ICANS is also something which is seen with other CAR T-cell therapies. Our incidence is quite low at less than 10%.

And potentially a more frail patient population, too, that could be more susceptible to those. I know we go back and forth with the existing data all day, but let's talk about PINNACLE, and then we can move into the second-line study. Just to level set for those in the audience, can you describe the third-line-plus study that you have ongoing in the PINNACLE trial?

Yes, so we have a really thoughtful clinical development plan where we have what we call our fast-to-approval strategy. We want to be first CD1920 on the market. It's called PENICLE. It's a single-arm study, which is really a seamless expansion from the third-line cohort in the phase one study. So it's just continuing on. The patients that we presented in the third line last year are part of that pivotal trial, which will continue on until we complete an enrollment of about 100 patients. So that's really our FAST2 approval study. We're presenting an update in the second half of this year. And then we're going to complete enrollment and expect to have the BLA submission next year with the data, the pivotal data being available mid-next year. So we're in a really great place to have this FAST2 approval strategy. The FDA has given us regenerative medicine advanced therapy for that third line plus indication. But in addition, we also have a pivotal trial ongoing in the second line, this head-to-head CAR T-cell therapy trial. And so we've positioned ourselves in a very positive way. But Pinnacle is our lead program, which is, we think, going to establish us as the first-in-class CD1920.

Yeah, and as it relates to Pinnacle, you mentioned you're going to have an updated data set in the later part of this year. There is a big medical meeting that focuses on hematology called ASH. We'll see if it's there or not. I'm not going to ask you to answer that question. But when we get that updated data, what are the key metrics that you'd point investor attention to as it relates to continued confidence in the profiles as you move into the final data set from Pinnacle in the middle part of 2027? Sure.

So last year we presented about a third of the patients. As I said, this pivotal trial is continuing to enroll. And so this year we expect to present data in more than 50% of the patients, so well on our way to the pivotal data set. And what you're looking for here is, of course, consistency. Where is the complete response rate? What is the median progression-free survival? How is this product performing over time? And I think the hallmark of a great product is it performs consistently over time. So that's what we're looking for.

Is there a specific bar? Is it really its overall response rate or median PFS that you're looking at internally as the critical outcome for success?

Well, you know, what's really interesting is the bar is, of course, I mean, the approved CD19 cars. And I told you their response rate in this line of therapy is about 50%. So we want something 60% or north. And I told you what we had last year was 76%. So that puts us in a good position. And for median progression-free survival, they're at six to seven months. We had 18 months last year. So we're well above any bar that one might set or, quite frankly, that would be required for approval in this space.

Yeah, I think consistency is a great way to put it in that you'll have greater maturation of the data set, too. So you have greater confidence in the numbers as you move through this readout as compared to the less mature existing data set, which is always naturally the case as drugs are developed.

Yeah, and this will be really the last look at the data before the pivotal data come out mid-next year. So it's going to be a really important data outcome.

And you alluded to, I think it's a 27, second half of 27 potential BLA and an approval in 2028. This is in the third line plus setting. A lot of people will think that, you know, in second line, autologous CAR-T is now kind of the standard of care. But is that necessarily the case? Are some people getting bridging therapy? And how do you think of the commercial opportunity within the pinnacle setting?

Yeah, so many people think that the third and later line is a smaller indication. And second line is really where most of the patients are. Because, in fact, CAR-T cell therapy is recommended in the second line. and that's where most patients are intended to be treated. But in reality, what happens is we know from data that 50% of patients who hit the apheresis chair, the leukapheresis where they collect cells for CAR T cell therapy, 50% of patients who receive CAR T cell therapy today have had two regimens of chemotherapy. So that means they would be third-line patients and on-label. So 50% of the lymphoma market today, which is about $3 billion, would be third or later line based upon having received two prior regimens of chemotherapy. We've confirmed this actually in a Medicare, this was retrospective data from Memorial Sloan Kettering, but we've confirmed it in a Medicare fee-for-service claims analysis which showed very similar results. So we believe this third or later line population is actually quite large, and we're very excited and then about 50%.

And then maybe just to round it out as it relates to the pinnacle setting, are you also pursuing it in a broader swath of patients in that you have older patients in the trial as well, and that maybe isn't an area where the autologous CD19s have gone into quite yet? How do you think about the breadth of the label in the third line plus setting on a relative basis?

It's always really important to compare patient populations, but our product, we have no upper age limit, so we successfully treated patients who are 75 and older I think that that's something that when you look at the randomized controlled trials for Brionzi, for example, they didn't include any patients over the age of 75. And so that's something that we're able to do.

And so the other trial that you alluded to was the Pinnacle head-to-head trial, which is quite an innovative design. Maybe just a level set, could you give a little bit more context around the design of that trial in the second line and what you're looking to achieve with that site?

Well, we call this our leave no doubt strategy because it is a superiority trial. That is, you know, the way we believe this market is going to evolve is that our CD19-20 Rhondocel is going to displace the currently approved CD19s. And so we wanted to provide the data to ensure and leave no doubt that that was the right decision for physicians and for patients. And it's important to know that in this marketplace, the physicians who prescribe CAR T-cell therapy are, of course, very data-driven. They are loyal to CAR, but they will switch CAR T-cell therapy based upon data. And we know this from the lymphoma marketplace, where, yes, CARTA or Axissel used to be the market leader, but they have lost substantial market share to Brionzi, or Lysacel, as Brionzi has a better safety profile. So based on that better safety profile, physicians are changing. We know in myeloma, multiple myeloma, for example, that ABACMA was the market leader, But when Carvicti came on the market with a much better efficacy profile, physicians switched. Well, now we intend to bring Rondecel to the market with better efficacy and better safety. And so this is a place where we believe that with the third line data set and then the randomized controlled head-to-head trial, we'll be able to switch out the CD19 cars. And when you think about it, once Rondosol gets into place in these centers, we've got a 76% complete response rate, assuming that data holds, with this very long duration of response and, you know, no grade three or higher series. It's going to be very hard to displace us. And so that's why the fact that we're first in class is so important right now.

Yeah, you're potentially consuming all of the headroom. You're really moving the standard of care forward. And the standard of care has progressed meaningfully with these cell therapies over the last five, ten years. As it relates to Pinnacle head-to-head, you say it's a leave-no-doubt strategy. What do you expect the comparator arm to be comprised of? I know you mentioned the market is shifting towards Brianzi from Axis L. Do you have any thoughts on the early composition of Brianzi versus Yescarta?

Yeah, it's a little bit hard to say definitively because, of course, as we said, market share is shifting. So we expect to see more Brianzi use. Our footprint is largely in the U.S. We also have sites in Canada and Australia. We think the majority of the patients will be Brionzi, but with a substantial share from YesCarta because we do have U.S. sites that are very much YesCarta users, as well as Canada and Australia. So we think it'll be a mix, but with a little bit of preponderance with Brionzi, which is great. And I think this is a real-world study where physicians were going to be studying this product to bring physicians meaningful data, which represents what they're doing in practice today. because most centers use both products and they select the product that they're going to use based upon the patient that's in front of them.

And one of the questions I get on the Pinnacle Head-to-Head study is that it's a very innovative trial, but it's a lot of cell therapy and cell therapy costs a lot to produce in that you have a cell therapy control arm and a cell therapy active arm. It's very innovative in that way. Can you talk a little bit about the measures you put in place to mitigate cost of the trial and some of the insurance preauthorization that you have and the enrollment criteria here?

Sure. So we have designed this trial to be very much, as we were just talking about, according to standard practice. The comparator arm, YesCarta or Brionzi, depending upon what the investigator chooses, is on label for the product. And so that arm is reimbursable. The product, the administration, in fact, in many cases the adverse events are reimbursable under Medicare or even commercial insurers because it's a well-designed clinical trial using product on label. And so that's been a substantial help to us. Of course, we're paying for study infrastructure for both arms. But this really helps defray the cost of the trial.

And we're expecting an update from the study later this year. It's framed as a broad update. Any more context you want to provide around what we should expect as you provide an update?

I think we're really just looking to demonstrate the momentum in the trial. I think we've heard repeatedly from sites and investigators how pleased they are with our study design, and particularly that it gives them the data they want for their patients and for themselves to make this switching decision. And so it'll be largely to give investors some signs of the momentum in the trial and the progress that we're making.

Great. Well, we'll look towards that and also the data update from Pinnacle as it relates to Rhonda. So at this point, I'd like to transition the conversation to Lyle 273, if that's okay with you. So level set, Lyle 273 is your GCC targeted CAR in metastatic colorectal cancer. This is a really high unmet need. Maybe you could talk broadly about what you've seen from this asset so far to date in this high unmet need.

Yeah, well, let's back up and talk a little bit about it. So this is a very special and novel CAR T-cell therapy for patients with metastatic colorectal cancer. As you spoke about, the unmet need here is tremendous. There is actually a a surge in metastatic colorectal cancer, very specifically in younger patients. And patients we're talking younger than the age of 50. And so this is a place where not only are the patients younger and the population increasing, the treatment options as they progress on their journey are very limited. And so when you look at the approved products in the third or later line metastatic colorectal cancer for those patients, which is where we're studying our CAR, They have response rates of 6% or less. They have six-month median progression-free survival or less. And their overall survival is less than a year. So the outcomes for these patients are very not good. And having a CAR T-cell therapy that could give them a one-time treatment to give them some relief from the progression of this disease would be really, really important so they can get back to their lives, to their kids, to their work. And so we have been tracking this very particular target for our CAR T-cell therapy, GCC. It's guanylil cyclase C. It's a really important solid tumor marker in colorectal cancer because it's expressed in more than 95% of colorectal cancers and their metastases. So it's a great target. We came across a paper in JAMA Oncology from a company in China that had developed a really novel car where they had GCC as a target, but they were coupling it with CD19, which is a B cell target, a heme malignancy target. But the CD19 CARs release cytokines, or I think these supportive hormones, when the CAR T cell is activated. And what the inventor thought of was this idea that we've got a great target, but in solid tumors, CAR T cells oftentimes don't expand enough. They get exhausted and die very quickly. And so by coupling the GCC car with the CD19 car that makes these special hormones, we could get great cell expansion, get an infiltration into the colorectal cancer. And more importantly, they presented data on 15 patients that showed a 40% overall response And that got our attention. Liver metastases that improved in patients, which are very difficult to treat. And so they, this Chinese company, brought this product to the U.S., got the Dana-Farber Cancer Institute and University of California San Francisco to participate in a clinical trial and presented data on 12 patients at two doses that replicated those results and showed a 40% across both doses, excuse me, a 50% overall response rate across both doses. So this is an active car, and we were super excited to bring it in at the end of last We are busy working to develop it. We're continuing dose escalation. We want to find the right dose for patients and to really manage the one safety sign that we've seen, which has been GI toxicity. It turns out normal bowel does express low levels of GCC, and so we have seen some diarrhea and some colitis, which we're working to manage. So this program is ongoing. In fact, we've expanded out the phase one, two. We now have more sites participating. We've added more cohorts, including a second-line cohort, and we're busy getting ready for an end of phase one meeting.

And you've added a new protocol to help mitigate against that GI toxicity. Maybe could you just talk through a little bit about the history there, what you did to mitigate it, and where it sits as it relates to the more recent safety data that you presented in the first half of this year?

So there was a patient who had quite significant diarrhea colitis and got treated with a lot of immune suppression. And so the patient actually got an infection and died, which was a really bad outcome. What's important to note about that patient is he had very widely metastatic colorectal cancer. And at autopsy, after getting his GCC car infusion, there was no evidence of disease. So this is an active car. What has to happen is we obviously need to manage diarrhea colitis. And so we implemented a prophylactic safety regimen where we use three treatments, vetalizumab and fliximab and budesonide. These are treatments that are known to protect the gut from colitis in advance of symptoms. And we were able to show that we could decrease diarrhea, grade two or higher diarrhea and colitis from 55% down to 10%. So really helped with that. And again, we're continuing to optimize now the dose and also the safety management plan. And then finally, I'm proud to say we just announced last week that we have successfully transferred this manufacturing process to our life manufacturing process. One of our critical success factors, as I sort of said early on, is that we own our own manufacturing center. And so this is a process which now we can bring in there. It's largely automated. We've improved some of the analytical methods and the process of that. And so we will now be getting some additional data with that manufacturing process.

Yeah, that's a huge accomplishment. Congratulations on bringing that manufacturing internally. As you continue to dose escalate, are you expected to see the similar potency with the internally manufactured product as compared to the externally manufactured product? Or is there any potential improvements in potency that you could get with a new process internally?

Yeah, I think it generally is comparable. I mean, that's our goal, but I think what we have done is we have improved the cryopreservation step. We have sort of a Lyle-optimized cryopreservation step, and so we just wanted to kind of improve, you know, cell viability, for example, and decrease apoptotic cells, and so it gives cells which are not as healthy, and so it could give us an opportunity to get even better benefit, and so we want to take a look at that.

Is that on the back end or the front end?

It's on the back end.

Okay, so the shipment of the cells could be more streamlined. As you look at a commercial setting, having a better crier preservation could allow for a greater shelf, like, quote-unquote shelf life.

Yes, it's always a better thing, yes.

And so you're continuing to enroll patients, and I believe you're going to have a data update in the first half of next year or early 27. You can correct me on that. Anywhere in 2027. What's the key factor to keep an eye on as we look towards that update? I know you've had some very encouraging early efficacy results. How should we think about interpreting that data?

Yeah, I think, again, the work of Phase I really is to optimize dose. So what is the recommended Phase II dose? That's a really critical step we need to define before we take this program to the FDA for the end of Phase I meeting, which we are looking to do. And then that really defines our path forward. And as we talked about in metastatic colorectal cancer, these patients have a very dire outcome. So this can move quite quickly. We want to just make sure that we get the dose optimized before we move forward.

And would you expect potentially a single-arm study? I know a lot of early cell therapy programs in Hemonc have been approved on single-arm studies. Colorectal cancer is a novel area for cell therapy, and it's a solid tumor. What are your thoughts on the regulatory pathway here? I know there's probably active discussions to some extent.

So the regulatory pathway in the past has been randomized controlled trials because, as we talked about early on, there haven't been products that have brought higher response rates in these patients. And so one of the conversations will be, and why we want to put our best foot forward at this meeting, will be, would a single-arm trial suffice? As we've talked about, we've expanded our trial to become a seamless phase 1-2 design, much like we talked about with Rondecel. So that's an opportunity for us. It's also an opportunity to do a randomized control trial, which might be for overall survival. And one of the things we've seen with this product is, again, a very robust overall survival, particularly for the patients in China where there's been a lot longer opportunity to follow them.

When you think about a single arm study, is there a lower threshold of patients that you need for exposure? Have you thought about that aspect? If you're able to get this abbreviated single arm study approach, is there a minimum size of that trial?

Typically in oncology trials for single arm studies, they want to see about 100 patients treated if that's sort of what you're asking. Yeah, how many patients. And so you can generally maybe get approval with a little bit less if the results are robust. But I like to think generally about 100 patients.

Great. And then maybe just to round it out on colorectal cancer, we talked about CD19, autologous CAR-T being a good comp as it relates to the commercial potential for RON to sell. What do you view as the external comparison for the commercial potential of Lyle 273? How large is this market, I guess?

So, yeah, this is a large market. There are 150,000 new patients diagnosed in the U.S. alone each year with colorectal cancer. There are 50,000 colorectal cancer deaths. So the number is very likely to be closer to that 50,000. So let's call it 40,000 patients a year just in the U.S. This is a huge market. And again, as we talked about surging in young people, this is a program where sites and patients are seeking us out because there is so little to offer patients. So this is a large market, and cell therapy is really very well positioned for these patients.

That wraps up a lot of questions I had. Maybe just to round it out, can you touch on the cash position of the company and the key catalysts that are encompassed within that cash position?

As of our last Q, we had $228 million, which gets us into Q3 of 2027, which is important because it gets us through multiple data milestones, including the data update in the second half of this year which we said is a very important data update on our pinnacle pivotal trial where we'll be presenting data from a majority of the patients observed and then also through the pivotal final pivotal data set that we'll be using for BLA submission which we expect mid next year great Lynn well we covered a lot of ground I don't know if there's any other closing marks you wanted to pass along but if not I appreciate everyone for taking the time to attend all right thank you appreciate the time.