Great. Good morning, everyone. Thank you so much for joining us. I'm Selvin Richter, a biotechnology analyst at Goldman Sachs, and really pleased to have with me the Lyell Team. Next to me is Lynn Seely, President and CEO of the company, and Charlie Newton, CFO. Maybe to start here for both of you, could you give us an overview of where your program is currently standing today and your key focus areas heading into the second half of the year and beyond?
Sure. Thanks, Selvin, and thanks to Goldman for inviting us. Lyell Immunopharma is on a mission. We're on a mission to develop next-generation cell therapies to give patients with cancer the time. We're working on developing one-time treatments using living cells, the patient's own living cells, to give them disease-free, treatment-free periods, a chance to get back to a normal life. Our lead program is LYL314 , which is a dual-targeting autologous CD19/ CD20 CAR T- cell, and it's in development for patients with large B-cell lymphoma. It is designed very specifically to give high complete response rates and long duration of response.
We're seeking to achieve that with our construct, which is a tandem CAR with, it's a true OR-gated CAR with full potency at CD19 and also full potency at CD20, again, designed to have higher complete responses because when you have, when you're approaching two antigens on B- cells, you can overcome antigen heterogeneity and also hopefully avoid antigen escape. Secondly, we select and enrich our T- cells in our final product to be enriched for naive and central memory T- cells, which we believe will give better engraftment, better persistence, lower cytokine release. These things come together, we hope, to really benefit patients with large B-cell lymphoma.
We presented our very first data from an ongoing phase I-II program at the American Society of Hematology meetings last year at ASH, where we were able to show a 94% overall response rate and a 71% complete response rate. Really nice data. I'm pleased to say that we recently submitted those data earlier in the year to the FDA, and we were given regenerative medicine advanced therapy, sort of the biologics equivalent of breakthrough therapy for small molecules, which was a nice validation of the meaningfulness of the data. We are looking forward to next week, which is the International Conference of Malignant Lymphoma in Lugano, where we will be presenting updated data, more mature data from this trial in the third line, and a sneak peek at the data from the second line.
The big news I'm here to announce for the first time today is that Lyell is officially in pivotal trials. We have recently completed a successful FDA meeting where we have a clear pathway to approval with a single-armed clinical trial in the third or later line setting, which will be a seamless expansion of the ongoing phase I-II clinical trial. Assuming we have continued robust data in that clinical trial and appropriate duration of response, this will be acceptable for a BLA submission. We are really, really pleased with that outcome. We are busy now. We have 16 sites enrolling. We are well on our way to opening up additional sites to get about 25 sites overall to complete enrollment of about 120 patients. Really big news for us to be in pivotal trials. I think additionally we are continuing the second line program.
As you know, we will be, we've committed to giving out more mature data in the second line at the end of the year. We are busy working on a randomized control trial in the second line. A ton going on at Lyell, a lot of momentum. We announced just yesterday that we've strengthened our commercial and clinical capabilities with new board membership and executives. We are well on our way building momentum.
Great. Charlie, anything to add here on the financial outlook?
I think the only thing I would add is that, you know, as we've talked about before, we're in a position where, from a capital standpoint, we're in the position to push forward with the pivotal study, both in the third line setting now and then moving into the second line setting next year in pivotals as well, and have the ability just to push forward and execute and not have to worry about raising capital anytime soon.
Great. Starting here, and you touched on this, but the acquisition of ImpactBio and its lead asset, 314, just maybe walk us through just to give some color about the strategy here behind this and what this means for your overall approach on the forward. What stood out when you looked at this asset to warrant investment?
Yeah. So really, Lyell has broadened its view from solid tumors to also include hematologic malignancies. Maybe, Charlie, I'll let you walk through some of the background to start about the acquisition.
Yeah. We had been watching ImpactBio for a while. I think the first time that we met with them, they had 10 patients' worth of data out of UCLA. We felt as though there was kind of a finite window from a risk tolerance standpoint where if the data were to mature, we would be very interested in being able to either acquire the asset or in-license the asset before it got so mature that a large pharma would be able to beat us to the punch. We continued to be in dialogue with them over the course of kind of the late 2023-2024 timeframe.
Once that data began to mature outside of just the academic setting into a multi-center study as well and saw some of those initial patients seeing data that was replicating what they saw out of UCLA, that gave us the confidence to move forward. From a strategic perspective, we really did think about it as expanding the aperture of what we can focus on. As you know, we have some technologies around solid tumors that we're very excited about and moving forward with some other targets that are in earlier stage clinical development. Those are obviously higher risk given earlier in their stages of development, but huge opportunities, commercial opportunities if we're successful. Impact, bringing that in, also a large market opportunity.
The CD19's doing kind of $3 billion or so in sales this year and going to $5 billion over the next few years, but much lower risk, higher probability of success at the end of the day for us to be able to get a product to approval and a product that we think will be highly differentiated in the ability to carve out a meaningful piece of that pie.
Maybe just to say, you know, this transition has gone about as seamlessly and smoothly as any that I've seen in my career, certainly, and really great credit to the team there as well as our team. You know, we have already tech transferred the process. You know, it started in an academic setting. ImpactBio really made a more mature manufacturing process. We have now successfully transferred that to our life facility where we have significant manufacturing capabilities. I think it really puts us in a good position. You touched on the International Conference of Malignant Lymphoma where you'll have data shortly. Walk us through the bar you're hoping to achieve in terms of durability to further de-risk this program. Can you just frame the overall release for the third line and second line to the extent you can?
Sure. I think when we presented our ASH data at the end of last year, 94% overall response rate, 71% complete response rate, people were like, "Wow, that's great." Where there were some questions, if anything, was just, "Well, where's the durability?" Right? The data were still immature. We only had at that point, I think, four patients that had data at six months. One of the things that's very clear in the field, the field is looking to get patients into complete response and then holding that complete response. Those patients who stay in complete response to month six and beyond, those are the ones that really are most likely to get this meaningful long-term disease-free, treatment-free benefit.
The question was, "Well, we need to see more duration of response." What we're really, you know, leaning into at Lugano, where we'll be presenting the next data, is looking at the six-month, the CRs who maintain it through six months. The bar from the CD19 CARs in the third line setting is about 40%. I think that's what we're looking at. They have about a 50% complete response rate, and then they lose about 20% of those by six months, leaving about 40% CR as the bar. I think people are looking to see how we'll look in the third and later line.
For maybe just overall for all these settings, like what is competitive with, you know, I guess generally what is competitive out there that could combine, that could compete with your drug?
Yeah. First and foremost, it's going to be critical for us to show benefit above and beyond the approved CD19 CARs. I think, you know, we are well-positioned to do that in several ways. I think our CAR was specifically designed to have high complete response rates. I think the bar with the CD19 CARs in the third line is about 50% and the overall response rate 70%. I think durability is obviously very important to these patients. Finally, safety. One of the things that we know is that to really provide accessibility in this marketplace, we want to see high rates of benefit to patients to encourage them to sign up for these products and then the safety profile that allows it to be more accessible in the community. That's what really we're driving for.
Maybe just to put a finer point on it. There is obviously a lot of interest in this dual-targeting approach. We saw some data at ASCO, and actually from one of Gilead's programs, we saw about a 78% ORR for their program. Can you speak to your differentiation on the dual-targeted side?
Yeah. First and foremost, we love the fact that the whole field is now leaning into the CD19-20 dual-targeting as a way to bring this next-generation CAR. We find it very, a lot of confirmation in our approach. The Gilead Kite product is a Bisystronic CAR. It is what I call a parallel CAR, whereas we have a single construct that has both the 19 and 20 binders. They have a 19 CAR that is very reminiscent of YESCARTA, and then they have a CD20 CAR as well. I think the efficacy data they put up looks strong. I think this is, again, very validating of the work that we are doing.
As you're looking at the benefits, I think it's very, or these candidates, it's very important to look at, you know, cross-trial comparisons are always enormously difficult, but you really want to look at the patient characteristics because they matter. One of the things that we have very specifically done is broaden the patient population that we're studying. For example, we don't have an upper age limit. When you look at some of the CD19 CARs, for example, in their pivotal data, they didn't allow patients older than the age of 75, whereas we're enrolling 80-year-olds in our trial. Patient characteristics matter. I think Gilead made a point of saying that they had a 67% response rate in their primary refractory patients. These are very, very difficult patients to treat because they never responded well to their initial therapy.
Looking at patient characteristics is very important as you interpret the data. I think overall they put up strong efficacy. I think their rates of Grade 3 ICANS and CRS were low, but I think, you know, it's important now that you have to have low rates across the board and certainly Grade 1, 2 matter. They had some substantial rates of Grade 1, 2 ICANS. All of this, the entire package of the overall safety, makes this amenable for outpatient therapy and, of course, the benefit to patients are what we have to look at.
When you look at this market, I guess how does this compare with the ability to maybe target CD20 after CD19, which we've seen some people do a kind of post-treatment approach here? Or how would it work in patients who've been previous, you know, your drug work in patients who have been treated by the existing CAR-Ts in the earlier line? Is there the ability to kind of come in at second line and treat some of the treated patients?
Patients who've been exposed to prior CD20 therapy, for example, antibody therapy or others, I think absolutely that's who we're treating today. I think we very specifically are going after a CAR-naive patient population because we think that's where the greatest benefit, I mean, these patients are really looking for an opportunity to be cured, right? The longer the disease-free, treatment-free interval, the better. Treating them in the second line with a dual-targeting product, I think, gives them great potential benefit. The CAR T- cell therapies have really, really put up strong data and particularly stronger than you're seeing with bispecifics. I think it gives us a tremendous opportunity if we're able to bring the right safety and efficacy profile.
Charlie, you might comment a little bit on the overall market and some of what we see with switching in this space.
Yeah. I think there's a question of who's the competition and then what's competitive in the market. I think on the what's competitive in the market, we feel as if we can show differentiated efficacy and/or differentiated safety that that could create a real opportunity for us to penetrate the market. I think you can look at the existing CD19s today and the success that YESCARTA had, well did the KYMRIAH, and then Breyanzi comes along with just better safety, not even better efficacy, and have really carved a meaningful piece of that pie and are expected to be the market leaders. We saw the same thing with that physician community in multiple myeloma and the CMAs with the CARVYKTI being the first one out.
CARVYKTI comes along, takes the market, and now, you know, big concern about what is our Cellex and Gilead going to do to CARVYKTI at the end of the day. That physician willingness, I think, to switch based upon better efficacy, better safety. We think that the profile for Lyell 314 has the potential to beat on both sides. We are very, very excited about that.
The overlay of bispecifics here in maybe just help us understand how you'd frame around that.
Yeah. You know, it's really interesting because if anything, I think the advent of bispecifics has helped us a little bit because it's, you know, made the community think a little bit more about being able to treat ICANS and being able to be more comfortable with CRS. I think CRS has become quite easily treatable, and I think most people, as long as it's low grade, are quite comfortable with it. I think they are now getting more comfortable assessing patients for ICANS. The answer is the CAR-T cell therapies just give much better efficacy, and it's a one-in-time treatment, and then you get this opportunity to be "normal" again if you're in that high percentage that actually gets good responses. I think we have a real opportunity here to make inroads.
I think accessibility continues to be a problem, but if we can have the safety and the benefit profile, it will give us an opportunity to move more and more into the outpatient setting, which will be important. I just, you know, this idea that, you know, CAR-T cell physicians are actually, you know, very devoted to CAR-T cell therapy, and generally they will give CAR before bispecifics. I think the point Charlie makes, but unlike other therapeutic areas, they're not so married to a specific CAR. They are very data-driven, and they want what's best for their patients, and they will switch readily across those. I think it gives us opportunity.
Moving over to your next-generation solid tumor efforts here. You're developing fully armored CAR-Ts for solid tumors. What lessons have you learned from your prior generation ROR1 targeting programs that you could, you know, apply now and you could use to optimize what you're working on?
Yeah. I'll say a few things. First and foremost, everything that we've learned in solid tumor cell therapy directly applies to what we're doing in hematologic malignancies. In fact, it's easier, right? The cell therapy centers are generally one and the same because the solid tumor patients, the autoimmune patients, the heme patients typically all funnel to these cell therapy centers. We're working with many, many of the same people, but hematologic oncologists are very comfortable with CAR T- cell therapy, unlike solid tumor physicians where you had to educate them much more. In essence, it's the same, but easier, I would say. We can take those lessons learned to help us, and again, just continue doing what we're doing, but a little bit easier.
I would say on the more next products for solid tumors, and I want to be very clear, we're super excited about our hematologic malignancy products, but we have not abandoned in any way, shape, or form solid tumors. There's a lot of inroads being made. I think one of the things we were able to do quite successfully with our ROR1 Program is to validate our anti-exhaustion technologies. We were able to see some partial responses in very sick women with triple-negative breast cancer. We demonstrated quite nice infiltration of our CAR T- cell therapies into the tumor and that we could, in fact, really reduce T- cell exhaustion. We had some safety issues. We couldn't get to dose.
What we've done is we've taken all that we've learned and we're retrenching a little bit, soon to emerge with what we call a fully armed CAR, where we're bringing to bear what we've already learned in terms of our anti-exhaustion technologies, our stemness technologies, and then also what the field has learned with respect to cytokine signaling and helping to overcome the hostile tumor microenvironment. We're going to bring this together and emerge with a new target for that.
If you look backwards at your prior program, right, what do you think would have, what do you think could have resulted in a positive trial? Is it the technologies here in dealing with, you know, being able to kind of overcome the immune aspect of it, or was it much more, is it like, is there an expression dynamic that's playing out with ROR1 and solid tumors? Like, I'm just trying to understand what could have been optimized.
Yeah. I would say, and you can sort of see by the way we're retrenching and coming back, is I think target matters. I think that was maybe we have an opportunity to find a better target that has got even higher expression in the cancer and lower expression in normal tissues. I think the technologies, clearly the anti-exhaustion and the stemness technologies, are important, but I think something to overcome the hostile tumor can be very synergistic with that. In CAR, everything matters, right? The CAR construct matters, the target matters. The technologies to enhance the CAR's ability to kill are important.
Can you also describe the technologies in particular with regard to what you're employing here, whether it's c-Jun over XRNR and R4A3 knockout, FER and SIMR, and, you know, how you're going to kind of bring these into the various programs?
We have not disclosed exactly. This is obviously a highly competitive field, but I think what you can expect to see is some familiar anti-exhaustion and stemness technologies as well as some new technologies to address the hostile tumor microenvironment. It will be a mix and then with target.
When might we see data from this program next?
We have publicly guided that we'll be filing the, or submitting the IND next year. Coming in the not too distant future. Again, in the near term, I think we're really focused on moving forward with more data with 314. I think as Charlie sort of alluded to, this gives us a really great position with now a pivotal stage program to move forward with that. I think a couple of things that made a huge difference for us in just getting through our most recent FDA interaction. I think there's been a lot of concern about how the FDA is going to look at cell therapies moving forward. I think we heard a very more optimistic than expected KOL FDA listening session. There are going to be more this coming week and beyond with CEOs.
There is an openness, and I think certainly we saw that with this ability to move forward with approval with a single arm trial in the third or later line. And, you know, we agreed on several things. We agreed on the dose. We agreed on safety monitoring, including the ability to dose in the outpatient setting, which I think is obviously quite important, and the endpoints of overall response rate and duration of response. I think this all puts us in a really great position moving forward.
Now how about manufacturing? When you, you know, when you look at all these programs you're conducting and you're in a pivotal trial, how are you preparing for not just the clinical aspect, but also the commercial?
Yeah. Our live manufacturing facility gives us plenty of capacity both for clinical as well as early commercial launch. We think with the way that it is currently constructed that we could manufacture upwards of around 1,200 doses per year. If you think about the existing market today, as I mentioned, about $3 billion in sales per year, I would tell you kind of 6,000-7,000 patients are being dosed per year with CARs today. You know, in the U.S. maybe is half of that. It gives us a big slice of that pie. Again, you know, ZIP code 30-40% of the market that we could penetrate just with that facility. Now as we get closer to commercialization, obviously we will be thoughtful about how do we expand.
We can do a significant amount in the life facility initially, but we'll undoubtedly want to expand further, and we could do that through CDMOs, potential building another manufacturing facility, even a partner at the end of the day. It is a relatively simple manufacturing process, so it gives us a lot of flexibility and latitude in how we think about doing that.
Right. Is there anything that you want to touch on with regard to the portfolio beyond here or just the strategy with these programs that we didn't speak to?
I think maybe just to say that, you know, we are very focused on the hematologic malignancies for 314, and I think that both of us as a company and to manage our expenses. We also believe this program has great opportunity in autoimmune disease, and something to consider for the future as the autoimmune field is really getting up and going. Nothing we're focused on right now, but an opportunity for us moving forward. I think, you know, we've got this third line pivotal trial, which is going to be this seamless integration with our phase I-II. We do believe we'll be able to include the patients that we have already enrolled or many of them. I think then the second line is really important to us because that's a major part of the market. We are moving forward very aggressively in that space.
I think for us, focus is important. Speed and execution are very, very important. This, as you know, opens up over time, and there are a lot of other places where this product could be potentially useful. This is sort of our heme focus, but then to your point about solid tumors, the day of solid tumors is coming. I continue to firmly believe that, and the field is making, and we ourselves have contributed to that, making great progress. We are really excited about that next evolution in our journey as well.
Maybe a last question here. You know, you brought in, you acquired a company and you brought in an asset, and obviously if successful, right, ultimately and it gets to the market, it can kind of fund your research for everything else. Are there, I mean, just given what's happened to the cell therapy field, are there other kind of interesting assets, or does it make sense for you to kind of consolidate some of these as you grow?
I would say we're constantly looking for opportunities, and that's frankly what brought us the ImpactBio asset. You know, we're always meeting with companies trying to understand what's out there, what's interesting, what may be competitive, not competitive to us, but competitive in the market ultimately. We keep our eyes open, but we're very focused on making sure we keep our expenses under control and given the current market environment being very disciplined about that. Would we bring something else in potentially, but it'd be a really high bar, I think, given the distraction, given the capital scarcity and the need to really focus on our lead program today.
Great. With that, thank you so much.
Yeah, thank you.
Thank you.