Hello, everyone. My name is Mitchell Kapoor. I'm a senior biotech analyst at H.C. Wainwright. Thanks for joining our cell therapy day at H.C. Wainwright. Our next fireside chat is with Lynn Seely from Lyell. Lynn, thank you so much for joining us.
Thank you for having me. Delighted to be here.
Maybe just to start off, as always, for those who may not be up to speed on the story, just give a brief overview of Lyell and the current initiatives. Then maybe we could just segue into the most recent update, the safety update for the LYL273, and just go from there.
Sure. I'm delighted to have a chance to tell you about Lyell. We have two clinical stage next generation cell therapy products in oncology. The first is ronde-cel, which is a dual targeted CD19, CD20 CAR T-cell therapy for patients with large B-cell lymphoma. We're in pivotal trials for that. We have two pivotal trials ongoing. One, a single arm study, which we expect to submit for BLA, the data from that, next year, so barreling forward. Then we also have a first of its kind head-to-head clinical trial ongoing for ronde-cel in the second line. A really exciting program leading the way for the CD19, CD20 CAR T-cell next generation class. In addition, as Mitchell was just referring to, we have LYL273, which is a very novel CAR T-cell therapy for metastatic colorectal cancer patients.
This is something that we licensed in at the end of 2025, based upon data from China, a single center study in China that was published in "JAMA Oncology," 15 patients with metastatic colorectal cancer in the third or later line, late line patients with a 40% overall response rate and a median overall survival across two dose levels of almost two years. Really quite remarkable results. This program was brought to the United States, and actually, when we licensed this program, data from 12 patients with across two dose levels, overall response rate of 50%, and again, really nice results. There was one case of high grade diarrhea colitis in that program, in response to your question, we recently gave a safety update from that program where we spoke about the safety from the ongoing clinical trial.
When the high grade diarrhea occurred, we put in a pretty stringent both GI prophylaxis and safety management plan that we could mitigate that risk, and we wanted to give investors some comfort on how that was going. We presented data from 10 patients who had GI prophylaxis to compare with nine patients who did not have any GI prophylaxis. What we were able to show, I'm very pleased to say, is we had a really nice decline from 55% Grade 2 or higher cases of diarrhea, down to just 10%. Something that was really quite manageable. Sort of as an overall benefit, in fact, there was no Grade 3 CRS seen, no Grade 3 ICANS, as well as no Grade 3 or higher diarrhea or colitis seen with the GI prophylaxis. We're very pleased with that.
Excellent. Great overview. Just wanted to dive in a little bit for LYL273. We're going to have efficacy data in the second half of the year, I just wanted to understand what investors should be focused on. Is it reproducing the 50% ORR across the first two dose levels? Is it 67% at Dose Level 2? More of a durability watch point for the 7.8 months PFS that we saw at the Dose Level 2 as well? Anything else that you would think that maybe we should be focused on?
Yeah. We did provide the safety update, but as Mitchell's alluding to, we have guided that we're going to be having a more fulsome update in the second half at a medical meeting where we'll be seeing both safety as well as clinical outcomes. We have, as I just described, some really nice data showing clinical activity, both from China that was then confirmed in U.S. patients. We're continuing to recruit this program and define the optimal recommended phase II dose, the question is, what's the bar for outcomes? I would say very unfortunately for patients, the bar is very low for late line metastatic colorectal cancer, which is what we're studying. I think in this case, if you looked at approved products for this patient population, response rates are 6% or less.
Median progression-free survival is six months or less, and median overall survival is less than 12 months. The bar is very low. We think, as Mitchell's alluded to, that we've already shown 50% overall response rates across two dosage levels, but the bar for approval is anything 20% or above. It's really quite low. We're very well positioned.
As you think about the regulatory path forward, can you talk about how that path has evolved, moving from the phase I to the amended phase I-II design? What are your planned key topics that you want to discuss with the FDA for an end of phase I meeting? Is it kind of the recommended phase II dose? The single-arm nature of a trial? What kind of things would you like to iron out with the FDA after you have data?
Great point. We did, at the time of the safety update, announce that we had amended this phase I protocol to become a phase I-II protocol. What that means is we have an opportunity to do a single-arm expansion into a phase II/pivotal trial if the FDA were to allow us to do a single-arm response rate trial. Now, overall response rates haven't been used in metastatic colorectal cancer patients, quite frankly, because therapies haven't been able to bring the sorts of response rates that the FDA might be looking for. In our case, that remains something that is a topic of conversation that we can have with them. One possible path would be a single-arm response rate trial. We have built that into this expanded phase I-II program, as well as looking at some additional cohorts.
Whenever you have the next step in a development program after phase I, it's an end of phase I meeting. We have guided that we expect to have that by the end of the year. Sort of as you alluded to, the number one topic for conversation is always, what is the recommended phase II dose? That is the work of phase I to really define that. What is the patient population? The inclusion/exclusion criteria. Of course, for us, what is the overall design? Because this is sort of novel territory in the setting that we are bringing a potential product candidate to them that may have an opportunity in response rate. We'll have to see what that discussion is. Of course, there is always the option of a randomized controlled trial with overall survival as an endpoint.
The FDA does offer, interestingly, through Project FrontRunner, an opportunity to do an accelerated approval pathway in such a trial using response rates as the accelerated approval endpoint within that initial trial. That's another interesting design that we can consider. It will be a really interesting conversation to see how that turns out with the FDA.
Yeah, that's great. I am wondering, in your view, what you think would be necessary to kind of demonstrate from an efficacy perspective in terms of overall, ORR, to justify a single-arm trial. Then, I think previously we had talked about some data from this asset that has had 25-month overall survival, I believe you had mentioned. Can you talk about how confident you would be in something like that, a randomized trial with an overall survival endpoint?
Yeah. I think both are possible. It really depends upon the conversation with the agency. Typically for response rate trials in late line oncology, we cannot speak specifically about colorectal cancer, response rates 20%-30% are generally required to allow that as an endpoint, and the agency has to be confident that it would correlate with better overall survival. I think we have talked a little bit that the bar for approval here, any response rate 20% or better would be great. For a response rate trial, I might set that a little bit higher at 30%. In general, something that is in the range of what has previously been seen with this product. It will be a good conversation to have.
I think the other thing, as you alluded to, is that the Dose Level 2 that was studied in China, granted it was a small number of patients, but they were very late line sick patients. The overall survival is 25 months. Again, if we can have the median overall survival currently for those patients in the U.S., third or later line is 12 months or less. We do have an opportunity with an overall survival endpoint as well.
Yeah. That's one of the interesting points for us, too, is the fact that you have kind of a large room for that overall survival to even move lower a bit, because you're doubling overall survival from-
Yeah.
Standard care.
That's correct.
Yeah. Why do you think that this solid tumor CAR- T is working the way it is? Solid tumors are so tough to treat, nothing has been moderately efficacious, and this looks quite remarkable. What do you think is doing the work for this asset?
At Lyell, we're very committed to developing next generation cell therapy for solid tumors, and we know it's been a challenge, right? Why is it a challenge? It's a challenge in solid tumors to get the CAR- T cells to expand well to infiltrate into the tumors. Quite frankly, the solid tumor microenvironment is very hostile, and the T cells rapidly exhaust and die. You have to get them to continue to live and thrive in this hostile tumor microenvironment. This product, LYL273, was very specifically designed to overcome those obstacles, it is a very novel design. First and foremost, it has a great target, which is known as guanylyl cyclase C, or GCC. It's a target that is overexpressed on 95% or more of colorectal cancers and their metastases. It's a great target.
It is expressed very little in normal tissues, just low levels in the GI tract, it's a great target. In this product, we couple it with CD19 CARs, not just any CD19 CARs. These CD19 CARs secrete cytokines. Think of them as supportive hormones that help these CAR- T cells expand. When we give this product to patients, the first thing that happens is it hits B cells circulating in the bloodstream. The B cells have CD19, when these CD19 CARs hit there, engage with their target, they release cytokines. This helps all the cells expand. We get nice infiltration into the tumor. Again, these CD19 CARs continue to secrete cytokines in the tumor microenvironment, which we believe helps really flip and warm up that hostile tumor microenvironment.
We believe it is this mechanism of the great CAR target, GCC, coupled with these CD19 CARs that express cytokines, which is the secret sauce here, which is giving us the type of benefit in solid tumors that we'd hope to see.
Can you just discuss where you are with your trial in terms of dose escalation and how you think about dose selection and the performance of the first two dose levels versus a potentially higher dose level? What would you be looking to see out of a higher dose level versus what we've already seen? Is it just finding that upper bound of what's possible? Could you just discuss what the rationale is for that?
The job of phase I is to find really the right dose to move forward. You want the best benefit for patients that you can get with a tolerable safety profile. Yes, we're continuing to recruit patients in the phase I trial, including dose escalation to get to that optimal dose for patients that we can then take to the FDA at that end of phase I meeting, which we've guided, we expect to have by the end of the year. We, again, are just looking for three things, right? The best response rates, the best duration of response with a very manageable safety profile, and takes some work to get that just right, but that's the job of phase I so that then this program can move very quickly, our hope would be through pivotal trials.
Okay. Can you discuss the prophylaxis regimen that you're implementing in the trial? How practical is that in the real-world setting? These agents, how familiar with them are physicians? Do you see this as a permanent part of LYL273 administration or do you think there'll be some changes in future?
Yeah. Great question. When we had this case of high-grade diarrhea, a significant GI prophylaxis regimen was put in place before any symptoms developed. Patients are getting infliximab, vedolizumab, and budesonide. These are immunomodulators, you might think of them of, that really protect the gut. Infliximab is an anti-TNF, vedolizumab is used to block integrins to protect the gut, for example, in ulcerative colitis. Budesonide is an oral steroid, basically, that's limited to gut exposure. As we've shown, very effective in sort of mediating some of the diarrhea that we saw earlier with our CAR-T treatment. These are commonly used treatments. They're well-tolerated by patients. There's nothing exotic or unusual about them, and something which I think are easier for patients to use. What we're working through a little bit now is what do we give upfront for prophylaxis?
What do we use for treatment as symptoms develop? I think, like all therapies, you've got to protocolize and optimize the safety management plan for them, and that's what we're trying to do because I think that will make this a very easy-to-administer product to really have the safety management plan protocolized, much the way we've seen happen, for example, with cytokine release syndrome in the lymphoma space with others. I think that's great. One thing about this product which is also very nice is there's only a single day of lymphodepletion, because as I alluded to, we want some B cells remaining to be circulating. This is actually quite an easy product to administer when you think of one day of lymphodepletion and then a single treatment.
We're talking about diarrhea, when you think about what these patients have to go through, this is an ideal treatment for them because it's a one-time treatment. If you have some diarrhea that lasts, let's say, for five or seven days, that's not the end of the world. When you think about chemotherapy that is ongoing over time, that sort of diarrhea side effect is a big problem. This is just a one-time treatment, it makes the toxicities much easier to manage.
Wonderful. Okay. I think it's important to talk about the modality here versus others that are being explored. As an autologous CAR- T, there is a process that's involved in terms of administration, and it's maybe a bit of an undertaking for a patient in late-line CRC. Given the context of what we've seen so far and the wiggle room you may have for data to change, what kind of magnitude of benefit would you imagine would be sufficient for a physician and a patient with late-line colorectal cancer to decide to proceed with an autologous CAR- T? Thinking about, for instance, the 7.8 months median PFS.
Is that something that's impressive to physicians and patients or would they, at the end of the day, from a commercial perspective, want to see overall survival, saying, "Hey, if I can live two more years, that's a compelling value proposition to me to undergo a treatment like this"?
Yeah. Well, a couple of things that are really important to know about colorectal cancer, and I have to say if ever there was a perfect indication for autologous CAR- T cell therapy, this is it. It right now is surging in younger patients, and people don't understand exactly why, whether it's processed foods or environmental toxins. The message is that the incidence of colorectal cancer in 35, 40 year olds, 45 year olds who are in the prime of their life is surging. These patients desperately want a one-time treatment so they can get back to their normal lives, get back to their kids, get back to their work, get back to their active lives. Ongoing chemotherapy is a problem, right? Because with ongoing chemotherapy is ongoing toxicities.
When you look at the products that are approved today, they're giving less benefit, but with ongoing cycles and ongoing toxicities. We actually think the opposite, that this is a situation where patients are actually going to really want this CAR- T cell therapy because it's a one-and-done treatment. As I said, as we get this management plan really protocolized and working out well, this is a pretty easy treatment because it is a one-time treatment with just one day of lymphodepletion. I think this is exactly what CAR- T cell therapy was designed to do. Be this one-and-done treatment so you don't have to go through chemotherapy and ongoing toxicities.
Yeah, that's very interesting. When we think about the patient selection for this and the trial design, can you talk about how you're thinking about liver metastases? Is that a restriction that you've put in there to more kind of homogenize the data where you can kind of see what the true effect is without some complicating variables? Or how do you think about patients who have liver metastases?
Yeah. One of the things that made us most excited about this product was the data, both from China and in the U.S., where patients have liver metastases that have, in one case that's published in "JAMA Oncology," completely resolved with this treatment. Liver metastases, as you may know, are notoriously very difficult to treat. What we have done in this particular trial is picked a, what I call a middle-of-the-road moderate liver metastases. We're not allowing patients with end-stage liver metastases to come in because that's very difficult to treat. We are allowing up to seven liver metastases, just none greater than 3 cm . Maybe allowing them, but keeping them in a moderate range so that we can really understand the benefit of the therapy.
Great. Okay. That's very helpful. I want to move on to a very prevalent topic in my investor conversations, in vivo CAR- T.
What are your thoughts on the in vivo CAR- T landscape? For shifting a little bit to DLBCL.
Yeah.
Ronde-cel autologous CD19/CD20 CAR- T, now we have in vivo CD19/CD20 CAR- T, albeit much earlier. Maybe you could start by framing how far ahead you are in the competitive landscape of CD19/CD20 CAR- T cells in DLBCL, just your thoughts on in vivo CAR- T and how that competes or is kind of separate from the autologous approach.
Yes, in vivo is quite a hot topic. Let me start, as you advised, with where we are with our autologous CAR- T cell program because this is here and now. We just presented safety data in 100 patients where we have no Grade 3 or higher CRS, single digits of ICANS, very well-tolerated safety profile with our next generation CD19 CAR- T cell therapy. We have presented 97% manufacturing success with a 16-day turnaround time, excellent availability of the product for the patient. At ASH last year, we presented 93% overall response rate, 76% complete response rate with, very importantly, 18-month median progression-free survival in the third or later line. Just for comparison, CD19 CARs have about six to seven months.
This is the best data that I'm aware of that's out there for large B-cell lymphoma patients here and now with great durability. Yes, in vivo is very exciting technology. We're very interested in in vivo CAR-T like many others, autologous CAR-T is here and now with a very high bar to beat. It's been around for a decade. We know a lot about the safety. We also know a lot about the durability, and this sort of durability is very important. We're all interested in the Legend data that is now put out CD19/CD20 in vivo CAR-T in six patients. Only three had large B-cell lymphoma, followed for two months. Interesting, this is not a competitive data set yet. Let's see what happens. In the meantime, ronde-cel is here and now. It's barreling forward.
We are going to have a significant data update from the ongoing pivotal trial. It's a single-arm study at the second half of this year, coming soon. We expect BLA submission next year. That's a really important milestone, and we are leading the way with the next generation CD19/CD 20 CARs. We think we're about a year ahead, and that gives us a great opportunity to really well position ourselves as the product of choice in the centers.
Great. Okay. As we look at the other autologous approaches, we had J&J, who recently kind of bowed out of the race it seems, and then Kite, who has changed constructs, CD19/CD 20 constructs, and is now a little bit further behind. How do you see the rest of the landscape beyond just Legend as the in vivo competitor? Obviously you're in the lead with the median PFS of 18 months. Again, we aren't also aware of anything better than that. How do you see the rest of the landscape and the ability to catch up or what the differentiation is whenever we look forward in a year or two?
Yeah. I would say right now we just don't know enough about the Kite product because, as you said, the data are very recent. I think we've presented data on more than 100 patients, so I think we have a very good idea about what our profile is. As I said, we think we're several months ahead if not a full year, which is great for us. I think this is really autologous CAR- T cell therapy is still, if you're a patient, you want the best outcomes you can get. Right now for patients, our product is being developed in patients for all ages. We allow bridging therapy. Again, it's the sort of product that I think it can be given in the outpatient setting, so patients don't have to go in the hospital anymore for that.
Right now, as of the last data presentation, 75% chance of going into remission, and not a short remission, but a really meaningful remission. That's, I think, what patients are looking for. We are working very hard to get this approved. We hope to be first. We know that physicians who prescribe CAR- T cell therapy will switch, and we believe they'll readily switch from the CD19 CARs to ours. We know that about more than 50% of patients who are getting CARs today, based upon Medicare claims analysis, have previously had two prior lines of chemotherapy, so we'll be on label for our third or later line population. That's a significant portion of the market with this fast to approval strategy. Once we're there, it's going to be very hard to swap us out because our data are quite strong.
We think this is a great fast to approval strategy for us and is going to bode very well in the commercial marketplace.
Great. I think the last thing I want to touch upon is the fact that right now, with all the things we talked about, Lyell is trading at a very attractive valuation. As investors look for inflection points, and what could cause the stock to kind of rebound, could you just highlight the year ahead, the next 12, maybe 18 months of data catalysts for Lyell and what investors should look forward to?
Sure. This is a great time to invest in Lyell, as I think Mitchell said. I think the stock is undervalued now. We have a potentially transformative data update coming with our colorectal cancer program. As we know, this is a large market with tremendous unmet need. We have a data update coming from our pivotal trial at the end of this year, which will be very nicely matured data, and will be the last look at the data before the data that we'll use for BLA submission. I think a great confidence builder for investors. Then, of course, next year we'll have the pivotal data from this program and be submitting the BLA, really gearing up for commercial launch. We didn't have a chance to talk too much about it, but Lyell has our own manufacturing plant. We are our own manufacturing facility.
We are running our commercial process as we speak, and we can launch this product with very effective and efficient cost of goods. This is a great marketplace for us. Again, we have the capabilities to support the commercial launch from a manufacturing position.
Wonderful. Thank you so much, Lynn, thank you to the Lyell team for joining us today. Thanks to all of the investors who dialed in for this conversation as well. Wish you a good day ahead.
All right. Thanks, Mitchell. Bye