Presented by their Executive Vice President of Kite, Cindy Perettie, who's in charge of running their CAR-T franchise. Cindy, thanks so much for joining us.
Thanks for inviting me.
I'm going to start with a multi-part question of something I think is on a lot of people's radars and minds lately with anito-cel, the BCMA CAR-T for myeloma. We just saw some updated data at EHA, and I'm curious how this frames your views on some of its potential advantages and differentiation from other BCMA CARs. First off, on efficacy, just, you know, some of the potential predictors of response there, extramedullary disease, number of prior lines, et cetera, what you think is most important that we should be looking for to compare your data set to other therapies.
When we think about safety, what do you think is the most likely reason why we're not seeing as many neurotox events, we're not seeing any Parkinsonism, you know, the degree to which this relates to better patient selection and prophylaxis, and your expectations for how that's going to hold up? I know that's a lot, but really it's about efficacy, safety, and how this compares.
I think maybe we'll start with the efficacy. If you look at the efficacy, and you're maybe able to see the abstract that we're going to be sharing more data at EHA in about two and a half weeks, the efficacy that we're seeing now, we've got about 12.6 months' worth of average follow-up for those patients. You're seeing a more mature data set, and we continue to see a nice high response rate at 97% for the overall response rate. We're also seeing our CR rate mature from what you saw at ASH, and we're at 68% on the complete response rate, and we expect that to continue maturing. On MRD, we saw 93% minimal residual disease, so we feel really great about this data.
You asked about how do you think about the various high-risk subgroups, and I would say take a look at our subgroups. We'll be showing that data with extramedullary disease, cytogenetics, and what we're seeing in those high-risk patients is we're also getting very consistent responses, and so we feel like the efficacy for this product is on par or better with what we see in the existing constructs in the marketplace today, and of course that data will keep maturing. The second piece was around safety, and so for our safety profile for grade three or above CRS or ICANS, we're at 1% or less, and what excites me about that is that can become an outpatient therapy.
If you think about patients who end up being admitted to hospital, it's usually from the grade three events that you see, and how we're looking at this is that we have an opportunity to reach more patients. We have not seen any of the delayed neurotoxicities that you see with some of the existing constructs, so no Parkinsonism, no Guillain-Barré. We haven't seen any of the cranial nerve palsies. In addition, we haven't seen any enterocolitis either, which is something that has been reported with some of the other constructs in this space. We're feeling great about the safety. We're going to keep looking. It's early days.
We have about 150 patients that have crossed over the four-month mark where we would expect to have seen some of these things happening, and we have not, but again, we will continue monitoring in ImagineOne as well as in the ImagineThree study that we have started. That safety profile, coupled with the efficacy, is something, again, I am going to stress, could make a very nice outpatient therapy, and as we want to reach more patients where they are, that becomes really important. If you couple that with our manufacturing today, we have three manufacturing facilities across our network, and we make our own viral vector, so we are moving the viral vector as well into our vector facility, but today we are producing anito-cel for our clinical trials out of our Maryland production facility, and that is also where we will launch out of.
Within the clinical trials, we now have more than a handful of patients on ImagineThree, and we're seeing those turnaround times in line with our commercial products, in line with the Yescarta and Tecartus timelines today, and our goal is to really meet that, is to at launch have that 96% reliability that we see with Yescarta and Tecartus, to be able to get our turnaround times down so that it's really meaningful for patients. We're excited about that. You asked kind of how do we think about the safety, and there's certainly a number of hypotheses floating around. We've spent a lot of time with our translational teams. We've been able to make the other two constructs within our research organization, and then looking at the ImagineOne translational data, and there's a couple of things that we notice that are different.
The first is, for those of you who've seen pictures of the binding domain of the D-domain, the D-domain on anito-cel is a small compact binder, and when I say small compact, it's helical in structure, and if you look at the other constructs that are available on the market today, their binding domains are quite large proteins that have integral folding, and what we found in mimicking cellular, intracellular uptake of these, we are not seeing the D-domain change based on pH or temperature or any of the things that would change physiologically in the body, but what we did see on some of the other constructs that we reproduced is we did see changes in the folds.
When we look at binding, in addition to that, we see a very fast on-and-off rate with the D-domain, and we think that that again mimics more physiological conditions. That fast on-and-off rate allows for really rapid killing and effective killing of the myeloma cells, but it also does not hang on and create the immunotoxicity that you see when something has really strong binding. Today our hypothesis that we are testing is really around the binding domain and our ability to not create those inflammatory and immunotoxic events that we are seeing with others.
Great, and what should we be looking for in this next set of data, and what's your sense of what would be required from a regulatory standpoint for approval in terms of just the magnitude of benefit, amount of follow-up, numbers of patients?
Yeah, so we're not commenting on the regulatory strategy per se, but I will say we continue to have engaging conversations with the agency around the ImagineOne filing, and we have all 117 patients now that we'll be sharing in the EHA data set, but obviously those patients would be maturing over time and would be part of the full regulatory submission, in addition to the phase I study that was conducted by our colleagues at Arcellx. We would be filing both of those data sets with the agency for the ImagineOne fourth line approval.
Got it, and you talked about manufacturing, and it sounds like you've been able to really leverage a lot of your Kite manufacturing facilities and expertise in this. What was the tech transfer like? Is that still ongoing at all? I guess where would you, it sounds like turnaround times are comparable to Yescarta. Where are you with regards to inspect rates? Is that something you would expect to be comparable, or just because this is a different product and process, we should be kind of thinking about this differently?
Yeah, our goal is obviously to continue to be leading in manufacturing and get to those places where we have the 96% reliability we have with Yescarta and Tecartus, and to do that, you obviously need high volumes, right? We've treated over 29,000 patients today with the two constructs that we have today, so there's also learnings that come from it. From the manufacturing standpoint, our tech transfer went really well, so part of a successful tech transfer we found is we have our research facility located near our Los Angeles production facility, so that continuity between your research and process development folks really matters.
Good news for us is Arcellx has their research facility located in Gaithersburg, Maryland, which is literally two exits from our Maryland production facility, so we had a really seamless, not just through the people, but also from the technology tech transfer, and that went really well. We literally had no hiccups, and I was waiting for something to come up, and we had none, and so the tech transfer is complete. Again, we're producing today out of Maryland for the clinical trials, and that's great that we're doing that because it gets us used to producing. It allows us to put in some of the automation that we wanted to put into that, so we're excited for launch.
Excellent, and as you think about launch, where do you see the highest priority market role for anito-cel? I mean, you sort of alluded to the outpatient opportunity, and even kind of beyond that, is there a certain type of center or a certain type of patient whose needs are not being met by the existing therapy? Where do you see this ultimately fitting in, I guess at launch and then down the line for earlier line patients?
Yeah, at launch, we'll be launching into that fourth line plus population. We get the question a lot, are there fourth line patients today? I want to remind folks that today for myeloma, only one in ten patients that are eligible are getting access to CAR-T, so there's still ample room for us to grow that, and we will. In lymphoma, it's two out of ten, and we know that we now know some of the pieces that are going to help move that market, which is how we get closer to patients in the community. 90% of myeloma patients sit in the community, only 10% in academic centers. Because it's a more indolent disease, they don't get referred till later, and reaching them where they are is important.
That goes back to my comment about having an outpatient therapy, so I just have spent about three weeks meeting with various authorized treatment centers and community practices across the U.S., and I know all of you meet with KOLs frequently, so I encourage you to ask the same questions that I'm asking. You know, when they look at the paradigm they have today for CAR-T in their institutions, many of them are treating with CARVYKTI, but treating inpatient, so in a certain number of days, the patient may be dosed, but they come back into the hospital. What I found on average was four to five days they're admitted.
The conversations we're having is they're not sure, you know, obviously time will tell if they even will need to admit an anito-cel patient, and that's something that they're thinking through, and certainly our clinical trial data will determine that, but bed space can become a capacity issue, and how we think about coming forward with an outpatient therapy and what that paradigm could look like is really important. We tested it in about 10% of our ImagineOne patients. We're looking at about 20% of our ImagineThree patients being treated in an outpatient setting, and we'll continue to collect data around that, but again, there is still a large unmet need.
The great thing about myeloma is there's been a lot of cool approvals in the last five to ten years, so there's a lot of therapies that physicians can work with, and what we're finding is you're seeing the quads move into front line, some into second line, and then the three drug regimens into third line, so there's still patients that have not received CAR-T by fourth line, and we really think we have an opportunity to treat those patients. A combination of the academic centers and our existing authorized treatment centers, as well as really pushing this paradigm for outpatient.
Today, we have 555 authorized treatment centers around the globe, so we'll obviously be able to use that footprint, and that footprint grows every year, so by the time we launch anito-cel in 2026, we'll presumably be in more than just 29 markets and have more than the 555 authorized treatment centers we have today.
Great, maybe speaking a little bit more about that existing footprint and the lymphoma space, Yescarta has been a miracle drug so far for so many patients, but there were also some challenges growing its use to the next level. As you mentioned, only two of ten patients. Can you talk about CAR-T franchise commercial performance as of late, particularly coming out of first quarter? What have been the key positives that you've seen, and some of the key challenges, and any kind of additional data you'd be looking at to help potentially re-accelerate growth?
Yeah, no, thanks for that question. As a reminder, one of the reasons I came to Kite is that we're actually providing curative potential for patients, so if I think about our second line data, we have four-year overall survival in 55% of patients. That's unheard of in that second line. In third line, it's at 43%. We've shared five-year overall survival data, and even in ALL, we're going to be sharing five-year overall survival data at EHA, but our four-year overall survival data in ALL is 40%. We know these drugs are active, and we know these drugs can have a profound impact on patients. Like you were saying, it keeps me up at night that we're at two out of ten patients, and so we have taken on a number of things to say, how can we make that look different?
I'll talk about quarter one, and then I'll go through sort of the activities we have. In quarter one, we continue to face headwinds both in-class competitors as well as out-of-class competitors with the T-cell engagers. In class, in the second half of last year, we saw a number of new approvals in the follicular lymphoma space, the CLL space, as well as ALL, and in those smaller tumor types is where we saw a lot of the headwinds in quarter one. Our Yescarta franchise went down 22%, so we took a big hit there in class and out of class. In lymphoma, we grew about 2%, so lymphoma we're seeing a little bit more steady, but with a new entrance of both bispecifics in the ALL, MCL space, and in-class competition, that's where we've seen a lot of headwinds.
We're going to continue to face those headwinds because we can imagine that you'll see additional approvals, but some of the things that we're doing to unlock that is then how do we reach more centers, how do we reach patients where they are? I've talked about this previously. My hope when I joined Kite was that we'd be able to move those community practices in six to twelve months, and what we've discovered is it takes a little bit more time than that. They have to work through contracting with hospitals and a number of other things, but we're starting to see some of that work go into motion where we're seeing more community practices now taking on CAR-T treatment and doing it either in collaboration with a hospital or one of our existing authorized treatment centers. The second piece is for our commercial payers.
Commercial payment is often tied to FACT accreditation, and FACT is an accreditation that goes along with transplant, and cell therapy was added to it. What's required to deliver a cell therapy is not the same as what's required for transplant, so holding that equal is really tough for a community practice who's never going to be a transplant center. FACT has created a modular accreditation, and they will be piloting across three of the large integrated community practices the second half of this year. We hope those will start probably in the late July, August timeframe, and we'll have data from that, and I think it's that type of work that will show that you can accredit a community practice that could apply more broadly, and I think having those large integrated practices showing it can happen is going to be hugely helpful.
We have a number of things going on on the policy side as well, but those are some examples.
Excellent.
We need to move lymphoma because we need to make room for anito-cel as well.
Good, and then on lymphoma, on Yescarta, Tecartus manufacturing, just maybe touch on the latest improvements that you're seeing there in manufacturing and turnaround time and where this may go in the future, and maybe also touch on the idea of kind of low dose three-day turnaround Yescarta.
Yeah, so for the existing products we have today, the improvements in manufacturing, a lot of it comes from automation, so becoming fully automated. Our Maryland production facilities are state of the art, and they operate primarily in fully automated, and we're bringing full automation versus semi-automation into some of the other production facilities, so that's a way we can make improvements, and we can make improvements on the back end on sterility testing. We learned so much during COVID, if you remember, we took sterility testing from seven-day plating to like one-day turnaround on sterility testing, so we're applying a lot of the COVID technologies to the back end of our analytics and testing side.
The second piece you brought up, we're super excited about, and so we have developed two products that look at a three-day manufacturing, so today manufacturing is anywhere from five to seven days of the product, and when you look at three-day manufacturing, you end up with more juvenile cells, so more naive cells, and these are more potent cells, and so one of the components of our next-gen products in lymphoma is that we have two constructs, one that looks just like Yescarta that has a three-day manufacturing process, and then we have a bicistronic, which is a CD19, CD20, so it's two targets and two co-stimulatory domains, CD28 and 41BB, and that's in three-day. We have one that's six-day and one that's three-day manufacturing.
We're going to show the six-day data at ASCO in just a couple of weeks, and then again at EHA and ICML, but the three-day manufacturing, it allows you to go in with anywhere from one-tenth to one-twentieth the dose, so really low doses, but showing very similar potent efficacy and much better safety, and if you think about going from a six-day manufacturing to a three-day manufacturing, right there is a savings in the manufacturing time, so we're looking forward to sharing data in the future on those products.
Excellent, and maybe speaking of the bicistronics, can you talk about maybe some, I know it's been tried before, but you guys have some unique elements with these specific co-stim domains that are, I guess, independent, coupling with the CD19 and the CD20. Can you talk a little bit about the properties of the construct, and then kind of what you're seeing profile-wise in terms of cell expansion and persistence relative to the sort of the first-gen CD19s?
Look at you, you need to come to ASCO and be our press for us. On the co-stim, the dual targets that we have, the bisystronics, we have done these, we call it a bicistronic construct. You really have two CARs that are pulled together by a linker. You'll also see in this space tandem constructs, so they're one construct with two targets, and what we've found in our own hands, and others may find different, is when you do tandem, you only have so much, our research head always says, you only have so much, sorry, you only have essentially so much that you can pack into a single CAR, so much real estate on that CAR, and by doing a single CAR in tandem, it's harder to get two targets in there most effectively, and even harder to get great transduction efficiencies.
We went with bicistronic, so a CD19 and CD20. CD19 has the CD28, so it gives you the sort of punch that you get with Yescarta, which is the rapid cell proliferation, but it's actually, when I say rapid, it's muted just slightly. You get to the same peak, but you get to it over time because of the 41BB co-stimulatory domain. You end up with the same number of cells, but the growth comes over a three-day period versus a 24-hour period, and why is that important? It's super important as it comes to safety.
You want to get to the efficacy level where you have the same number of cells being produced, but doing that persistence component of having it over time and having it hang around longer is what we're seeing with the 41BB, so we get a little bit of the best of both worlds. If you have a chance at ASCO, we're showing our bicistronic construct with our six-day manufacturing, it's called 363, and the goal of the bicistronics for us has been, we need to improve on efficacy versus Yescarta and existing products, and we need to improve on safety, so we're looking at both, improvements on both, and we're looking forward to sharing all of that data with you.
Excellent. You've talked a little bit more about potentially going into INI with CAR-Ts, and I know it's been an area where, you know, it's been tried, there was some initially a lot of excitement, and then maybe the next rounds of data hadn't necessarily lived up to the initial enthusiasm, and there's been challenges in enrolling patients and finding the right patients and indications, so can you talk about your interest in expanding the bisystronics to INI indications, what your current plans are, when we might see the readouts there, and how you maybe overcome some of the challenges?
Like, do you have some data that you're seeing on B-cell depletion inhibition that gives you confidence you're going to be at a level that's more successful, and/or are there certain indications that you will be going after that you think maybe others have not pursued where you think there's the most opportunity?
Yeah, and similar to sort of hematologic landscape, if you think about rituximab, it's used both in autoimmune, the CD20 target, I think about Okrevus and multiple sclerosis. We know that CD20 is active in autoimmune diseases, so that's one of the main reasons we decided to look at the CD19, CD20 construct, because we think having the opportunity to hit both, particularly if you have patients that end up having one or the other muted, you have a second chance, and that applies to oncology as well. As I look at the construct, and I described, we're putting our six-day manufacturing, the 363, the data we'll share in hematology at ASCO, we're putting that into, we filed the IND, and that's going into the rheumatologic malignancies, or rheumatology indications now, and our belief really is to test that hypothesis is, what is CD20 adding.
The second piece is I described the two co-stimulatory domains about reaching the same peak number of cells, but reaching it over a slower period, that matters in autoimmune disease. I mean, these are patients who are living with a chronic disease, we don't want to see safety signals in the line of what you would see in an oncology patient, it just won't be tolerated, and so that was another component of why we wanted to look at our bicistronic compounds, yeah.
Okay.
Yep. We started a rheumatologic, we filed an IND, we're starting a basket study where we're looking at lupus, both SLE and lupus nephritis, we're looking at myositis, and we're looking at scleroderma, and we're in the process of filing a second IND where we would have, we will look in neurological conditions, both myasthenia gravis and MS, and both of those we know have a CD20 component to it, and that's why it made sense to look at the bisystronics there.
Great, and when might we see any initial hints of those data, do you think? Is that sort of a 2026 event?
They're just getting started, so we'll keep you posted. As you said, it's become a crowded space, so we're looking at running our trials in a global setting in the U.S., Europe, and Asia, just to make sure that we can get a diverse patient population and understand not-seen differences, not end up having not-seen differences early in the phase I.
Good. Just in the last 30 seconds, anything that we did not touch on, on the cell therapies that we should be keeping an eye on, or that is maybe under investors' radars, but we should be?
Yeah, I would love to put in a plug for solid tumors, so we have an oral coming up at ASCO in a week in the glioblastoma space, so we have put together a construct with our colleagues at Penn that is looking at a dual CAR, which is an EGFR and an IL-13RA that we are testing in glioblastoma. I think we'll be sharing somewhere between 15 and 18 patients' worth of data there. These patients are heavily treated glioblastoma patients, probably coming up on second and third line, end of life, unfortunately, but the therapy is delivered through an Ommaya port into the brain. You don't have to lympho-deplete the patient, it stays within the CNS, and so hopefully you'll have a chance to come see that data.
We are working on a version two of that construct because we recognize from the data we see in phase I that we need a little more persistence. We want it to hang around in the CNS and still not have to lympho-deplete the patients, so we're putting armoring on that, TGF beta armoring, and we'll be testing that second construct in the coming year, but solid tumors are possible now.
We will look out for that data in the coming weeks for sure.
Great.
Thanks again, fantastic to have you here.
Thanks.
Thanks, everyone.