Welcome everyone. I'm Yigal Nochomovitz, Biotech Analyst here at Citi in New York. This is our February event, which is our Virtual Oncology Leadership Summit. We've been doing this for a few years, and have a great lineup today, and in this session, we have senior management from CRISPR. So we have with us Sam Kulkarni, who's the CEO, and Naimish Patel, the Chief Medical Officer. So welcome, both of you. And for those listening, remember, you can just email me, yigal.nochomovitz@citi.com, and I will relay any questions you may have over to Sam and Naimish if you have any. So obviously, it's an oncology event, but it's obvious that you guys do a lot more than oncology.
But that being said, maybe we'll focus the discussion there initially, and then perhaps broaden it, you know, as time permits to some other topics. So Sam, maybe if you could start, you know, talking about the oncology programs that you are engaged in, perhaps with the ex vivo program in zugo-cel, previously CTX112. You know, just tell us at a high level about the construct, about the design there, you know, what you sought to achieve to improve the properties of that cell therapy, and then we can move into some of the details in terms of the data you've shown and the plans for further development.
Yeah. Thank you, Yigal, for having us, and it's always a pleasure. As you mentioned, you know, at CRISPR, we're doing quite a bit across different disease areas. We have commercial product for sickle cell and thalassemia, together with Vertex, but beyond that, we have cardiovascular programs and a cardiovascular franchise. We have a franchise in autoimmune disease with our allogeneic CAR-Ts, and we have effort in Type 1 diabetes with regenerative medicine approaches, in addition to what we're doing in oncology. But I think oncology is still remains core to our efforts, particularly because we have what I believe is a best-in-class allogeneic cell therapy platform, and I'll talk more about that, with regards to zugo-cel and other efforts.
And we also have an emerging platform for in vivo CAR-T, both transient and permanent CAR-Ts, which can apply in autoimmune diseases and in oncology. So right now, what we have as our main area of focus or efforts in oncology relate to zugo-cel, and zugo-cel was formerly known as CTX112, which was a next-generation product after our initial efforts with CTX110, all this targeted towards CD19. And what makes zugo-cel special is that this is an allogeneic CAR-T.
In other words, it's a CAR-T made from healthy donor-derived cells, in our own manufacturing plant in Framingham, Massachusetts, and we've made advanced edits to these cells to make it much more potent than the first generation of allogeneic CAR-Ts, and almost get autologous-like efficacy, with a better safety profile that could have meaningful impact in heme malignancies, like DLBCL, but also beyond that.
Okay. I think it would be great if we could talk in some detail about those edits 'cause they're obviously important and unique, and how you effectuated them and what, you know, what properties they convey in terms of potency and durability.
Yeah. I'm happy to start with the edits, and I'll ask Naimish to add some comments as well, but the main edits we make with zugo-cel, some are required, which is you want to knock down. You wanna insert the CAR-T, obviously, which is the primary function, the primary way of making a CAR-T, but the way we do it is much more elegant than viral approaches. We actually insert the CAR into the TCR locus, so we get a double effect. We knock down the TCR, which prevents graft versus host disease, and we knock in the CAR into the TCR locus with endogenous regulatory control. Beyond that, we make edits for both potency and persistence, so we make an edit in the beta-2M locus, which effectively knocks out the components of the MHC Class I presentation.
So declaring these allogeneic cells as foreign, so if you knock out beta-2M, you don't have a flag waving that says that they're foreign cells, and you know, gives you more persistence because your host immune system, particularly the T -cells, will not eliminate these, allogeneic CAR-T -cells as fast as they would if they didn't have the beta-2M edit. And then, beyond that, we have two proprietary edits that are really important in making this generation of CAR-Ts more potent than the previous generation.
One is called Regnase-1, and this is a central mediator of cytokines, and various factors produced by the cells, and by knocking out Regnase-1, what you're doing is making these cells retain a more naive phenotype, which allows for more expansion and more durable effect, and reduces exhaustion in these T -cells, while at the same time, make them more cytotoxic. And that is an important edit that we validated, but others in the field, like Carl June, have validated as well. And the other edit is TGF-beta receptor 2, which effectively prevents TGF-beta-mediated cell exhaustion or prevention of potency from these cells. So those two edits confer significant potency.
So I guess the overall strategy, you know, we learned from our first generation CTX110, which is these cells, allogeneic cells are not going to last forever in the patients. They're, you know, without any persistence edits, they last about 15 days. With some persistence edits, like beta two, they last about a month. But the bigger issue was, in the month that they persist, they were not active the entire time because the cells got exhausted by day 11, day 12. And what we did is, by making these additional edits with Regnase and TGF-beta R2, we ensure that the cells are active all the way through the time which they have in terms of the persistence window.
So we effectively increase the AUC or the activity under the area for these cells in the time that they have to kill the cancer cells.
Okay. And in terms of—you mentioned it's donor-derived, so, you know, and it's allo, so how—you know, how broad of a population can you, can you cover with this, with this set of donor, donor-derived, batches? And do you have to deal with, you know, HLA matching or, or things of that nature as well, or not?
Yeah, Naimish maybe-
Yeah, absolutely. So, yeah, our studies thus far, we have not HLA matched, and we've seen no... But we do, sort of measure, HLA subtypes in patients. We haven't seen any correlation either between, HLA and, cell expansion. And so, so basically, there's no requirement for matching, and so there, there's no limitation in that, that way. And we've also redosed patients. So some patients who had a partial response to the first dose might get a second dose, to deepen the response, and we don't have any evidence to suggest that there's any, immune response or anything like that. So, it's a pretty nice system because of the, the, immune evasion edits that we've, put in, that it, that doesn't seem to be an issue.
Okay. And anything special on the lymphodepletion regimen that you need to do, or how does that part work?
Yeah, and part of the reason we did this is because we didn't want to—the, what other folks have done in this area is they've, to get better expansion and better persistence of the cells, they basically had greater levels of immunosuppression. Larger doses of the LD regimen or adding some sort of biologic to produce a long-lasting cell depletion. We use the standard CAR chem LD regimen that's used with autologous in oncology as well. And that's all—that's very sufficient.
And just to add on to what Sam was talking about, if you look at the expansions from the prior generation, CTX110, to now zugo-cel's CTX112, dose for dose, we're seeing a significant level of increased expansion at every dose. And at the highest doses, at the doses that we're taking forward to phase II, we see cell expansions akin to what's seen with autologous CAR, which was really the objective in making these edits. So we're very happy with what we have now, that we can at least equal the efficacy of autologous CAR but have the same treatment regimen.
Okay. So maybe, Sam, if you could talk just— You know, we got through the basics of the structure of the asset, but what about the strategy in oncology? You know, where do you— and you mentioned autoimmune, where do you want to take this asset? What are you know, what is your goal for how you want to develop it? Obviously, the allo market is extremely interesting in the United States to expand the reach of cell therapy to a much broader population. And, you know, we've seen those arguments made quite broadly by not only you, but others. So just kind of just walk us through the strategy here in terms of where are you going to focus? I mean, you have some early data.
We can talk about that in a bit, but you know, before we get to that, what's the long vision here for this program?
Yeah. I think for zugo-cel, we're very bullish on the program, and we believe it's going to have impact in both autoimmune and oncology. At this point, you know, in autoimmune, we're, you know, all in, in a way that we're rapidly enrolling patients, we're expanding the number of indications we're treating from lupus, myositis, and scleroderma, where we started to now include ITP and WAIHA, and we're probably going to add more indications because we just think allogeneic CAR-T is going to be the winner in autoimmune. The reason is as follows, which is, the cost of goods of allogeneic is sub $10,000. It's very scalable relative to autologous cell therapies, where we've seen remarkable data. Second is it's very convenient.
You don't actually have to stop the treatment that patients are on undergoing to harvest T -cells, like in autologous therapies, and that which may cause flares. So here, you can just continue them on and then treat them with the allogeneic therapy, and then pull off all the medications once the CAR-T's done its work. And the third is, we think the efficacy and potency is going to be equal, if not better for allogeneic CAR-T without any of the safety risks, like ICANS, that we've seen with some of the autologous therapies. And that's because, you know, these cells will get eliminated eventually after they've done their work, but you've caused the immune reset.
And the reason, you know, in autoimmune, we feel very good about it is, you know, even if you get 99.9% of the cells in autoimmune disease, you know, you basically reset the immune system, you know? In oncology, you have to get 100% of the cells, because even one cancer cell may come back as a cancer later on to get durable efficacy. But in autoimmune, I think, you know, it's very clear that allogeneic CAR-T can do the job, or allogeneic CAR-T can do the job just as well as autologous therapy. And it would be a very safe option for patients because the cells disappear after they've done their job, and you have lower safety risks in terms of ICANS or CRS at the dose we're expanding in.
So in autoimmune, I think we're all systems go. In oncology, what we need to demonstrate, you know, one is, yes, we get very high CR rates, but do you get durable CRs? And, you know, with CTX110, when we started off with the first-generation allogeneic CAR-T, we did get about 40% CR rate at the beginning, you know, in the first month. And then, but if you look at six-month CR rate, that number dropped to about 20%, you know, 'cause half the CRs were not... You know, the cancer's come back, and that's because the cells were not as potent. Now, what we see with zugo-cel is that we've pushed up the initial number quite a bit, you know, almost 70%, and I'll talk a little bit more about the data in DLBCL.
And we've potentially pushed out the durability as well, because you're getting very deep reduction, you know, almost MRD negative, in almost all cases, in terms of eliminating the cancer. And so we feel good about what the durable CR rate's likely to be, and we have this additional weapon now by combining with a BTK inhibitor, pirtobrutinib, that actually can ensure the durability. Because if there's, let's say we eliminate 99.99% of the cells, but there's one cell left, you know, that, you know, it'll get taken care of by the BTK over a course of maintenance. So overall, we think the, you know... On autoimmune, I think we'll have more data to show, but we feel very, very confident that this thing is gonna work, and it's gonna be a very transformative product for patients.
In oncology, we have to show a little more data, especially with this combo. We've already shown that the CR rate's much higher for 112, but if we can show that it's durable, then, then we have a winning product in oncology as well.
When investors-
Yeah, and-
So go ahead, Amit. Sorry.
Sorry, but just one. And, of course, the field is moving forward, right? So, there's bispecific autologous CAR-Ts showing even better, in oncology, even better response rates. So there's also some evidence to suggest that BTK inhibitors might enhance CAR-T cell activity during the expansion phase. So we're really targeting for even a higher efficacy bar with the combination than... Even our early mono data shows data that might be at least as good as an autologous CAR, a monogenic, but really the bar is getting raised, so we're really looking towards something even better.
Just when investors think about this program, I mean, are you kind of going parallel track here in oncology and autoimmune, or are you gonna make a determination which one to do? It seems like autoimmune is very much happening. Oncology, is that still you'll evaluate, you'll see how it... the data with the pirto potentially, and then make a decision? Or can you just talk about, you know, how you're gonna pursue both or one of these programs with this asset?
Yeah, yeah. Well, we're pursuing both in parallel right now. I think the key, not catalyst, but the key determination of how to move this forward is gonna come after regulatory discussions. And I think, typically, you know, RMAT is an important designation that these programs get that allow us to have very fluid discussions with the regulators as to what the path forward is. At this point, you know, what we've seen is that the FDA, in the U.S., the FDA have given very favorable guidance to companies in the autologous CAR -T space for autoimmune indications. You know, small trials that can get them to registration and approval.
And for oncology, I think we're gonna ask the same question: Can you do a single-arm trial that can get us to registration, or do you need to get, you know, do RCTs, which obviously make it harder to get to approval? And I think so, in autoimmune and oncology, we're parallel processing, and by the end of the year, we hope to have these discussions with regulators to understand what the path forward is. And at that point, we have to make the decision based on each indication individually, how does. You know, what is investment required, and how can we get to the finish line?
But at this point, I do believe that it's likely that regulators are, you know, allow a path forward that's not too burdensome in terms of registrational trial for both oncology and autoimmune indications.
Okay. So then let's talk about a bit on the autoimmune in terms of which indications you've explored. You've had some data, obviously, in SLE, but then there's some other studies. You mentioned ITP and WAIHA as well. Which, where do you see the most promising potential among these different autoimmune indications? Or again, is it just, you know, it's a data-driven question clearly, too?
Yeah, no, great question. I mean, I think just to add a little bit to what Sam was saying, I think the data we have today, both in oncology, suggests that zugo-cel is as active as an autologous CAR T. What that means is in the autoimmune space, that the efficacy is good enough to provide long-term remissions in a number of different diseases. In oncology, I think 'cause the field is sort of now even moving ahead there, we're looking for something a little bit more the combination therapy. But on the autoimmune space, you know, the key breakthrough, I would say, with CAR -T is the fact that Sam mentioned immune reset.
We're able to deplete the B cells so that the pathogenic B cells are all gone, and the B cells that return with CAR-T cell therapy are naive B cells, and they're no longer pathogenic, and patients can get long-term remission, without any background immunosuppression or any therapy. That's been shown very well for a number of years in follow-up, in Georg Schett's group in SLE and a number of other diseases. We have a rheumatology basket trial, where we're looking at SLE, inflammatory myositis, and scleroderma. We're now recruiting actively in all three indications. We've shared some... Our first couple of patients were recruited in SLE, and we've been able to achieve a zero disease activity, a SLEDAI of zero, in both those patients.
In one of the patients, we have up to 9 months of follow-up now off any background therapy with complete remission. So, and all the biomarkers, there's complete B-cell depletion at day 28. There's a good CAR-T cell expansion. It's all pointing in the same direction that we're getting the immune reset, so that's very exciting. So, we've already also started a second trial in ITP and WAIHA, and there's been some case reports, both from China and outside of China, in ITP, showing patients that are heavily pretreated and have failed multiple different MOAs, having lasting and durable return of platelet counts after CAR-T cell therapy.
Similarly, there was a recent patient also published in Warm Autoimmune Hemolytic Anemia, and these are spaces where we're not seeing other CAR-T players actively advancing. So it, it's a bit of a white space for us as well. But also, there's evidence to show that CAR-T-cell therapy, similarly here, provides that immune reset and long-term remission. So that's another exciting study that we've now kicked off and look forward to data in the second half of this year.
From looking at the data now, it looks like you have a, I mean, a very strong asset, right? I mean, even in these two SLE patients, it seems like you've achieved what you want to achieve, unless I'm missing something. It seems very good.
Oh, absolutely. We're there. There are a number of different places we could take the rheumatology side. There's SLE, there's inflammatory myositis, and scleroderma, each in their own are high unmet need indications. And then there's things like interstitial lung disease that cuts across all three of those things that are also incredibly high unmet need. We're definitely trying to target places where we could potentially be first. And so we're thinking very deeply, but we're very happy with the results we're getting. Absolutely.
Okay. So for a first sort of registrational trial, you want to offer any thoughts as to where you might go first? As you say, look for something that's less competitive, like, like an ITP or WAIHA or scleroderma, perhaps?
Yeah, I think all those things are on the table for us. I think that the data readouts that we'll have in the second half of the year, we'll have more patients across those things, will help guide the direction, but all those things are fairly exciting. And Sam, if you're going to say something as well.
No, absolutely. You know, one of the differences as we look at, you know, the autoimmune space versus what happened with oncology, you know, autologous and allogeneic are moving, you know, almost on par in terms of timing, right? You know, in oncology, what happened is oncology you know, autologous has started about six years before allogeneic approaches started. So it was a little bit hard to show, you know, in that patient population, how one's better or worse. But right now, we're seeing both of these move on par. The second dynamic that's very interesting is that, you know, there are trials out of China generating data, you know, that are almost like signal-seeking, that we can follow. So we'll follow our own data, but we'll also follow data that we're seeing from others.
And, you know, as Naimish mentioned, data on ITP and WAIHA coming out of China. So, you know, in Lupus, we're already getting sort of our best case, which is one patient's already at month nine, you know, it's SLEDAI zero. The second patient, that's SLEDAI zero and coming off the meds that they were on originally. And so, I think we're already seeing that. We just need a larger N in some of these indications, and we look forward to sharing that data second half of this year. And, you know, we have a lot more centers now enrolling as well, so that should pick up as we go along.
Okay. Okay, so data for me, some of those sub-studies or the basket trial in the second FDA?
Yes. Yes.
And then as far as doses and things of that nature, are you still in that exploratory? I know with these two lupus patients, you did 100 million. Are you looking to change that? Are you happy with that?
Yeah, no, absolutely. I mean, the things we're looking at is, but beside, because the clinical response piece takes a little bit longer, is looking at both the, the T cell expansion as well as the B cell depletion. And for both those patients, it was great, in terms of especially, zero B cells detected at day 28. So it certainly is a very active dose. I mean, the questions that we need to answer is that will that dose be the same dose across these indications, or would certain diseases require a different dose than other diseases?
Right now, we're all starting at the same dose, all indications, and the data will sort of drive that, but we're certainly happy with the B-cell depletion we're getting at 100 million, and that aspect of it should be similar across diseases.
Okay. And then maybe Sam or Naimish, the Lilly partnership on pirto, just tell us a little bit more about how that came about, and you have or have not generated any data there yet?
Yeah, you know, there was a paper, an abstract at ICML this past year by a group at the MGH and Brigham, where they combined a different CAR-T, an autologous CAR-T with ibrutinib, another different BTKi, and they were able to show, in LBCL, CR rates above 80% in that study, and that really got us excited about the prospects of the combination. There is some data, as I mentioned before, that inhibition of BTK enhances the CAR-T cell activity, preclinical data out there, and it made mechanistic sense as well.
And so, you know, we approached Lilly, who also was interested, and as I mentioned, the oncology, it's, and Sam mentioned this, it's a bit of a more moving target, right? Where the autologous CARs have been out for years, and now people are coming forward with bispecific CARs and doing RCTs against monospecific CARs, because the efficacy is that much better. That combination I mentioned, that efficacy is on par with a bispecific CAR. And so if we can reproduce that with zugo-cel and pirtobrutinib, I think we'll set up better to actually compete against what's coming down the pipe in oncology. And so the study's ongoing. We don't have data yet to share, but we're really excited about it.
This, you would do this study in the patients that are the second-line LBCL patients, or who would you target initially for this combo?
Right now, the study that we're doing, it's largely third line plus patients that are being studied, and it's very similar to the population that was studied in that Brigham MGH investigator-sponsored study.
Okay. And then if you were to move forward with a, you know, an approval with this, say, with this combo, that would be in that setting, or would you potentially go earlier and try to go up against, you know, maybe the second-line people that had failed in auto CAR-T in the front line? Would that be a consideration or no?
Yeah, I think, I think this is where I think we'll, we'll have to... It's gonna be driven by the data and the regulatory discussions. You know, I think, yeah, I guess this, strategically, what we could do is pick off a lot of niches, niche areas in this space because it's still a big market. For instance, what we could do is, you know, try to get approval with a single-arm study in relapsed refractory setting in third line, but then do trials, you know, for instance, in front-line ineligible patients or patients who are ineligible for CAR -T or TCE, and there are a lot of them that can't tolerate even six cycles of R-CHOP, for instance. There are patients who are, you know, ineligible for CAR -T in second line.
Because I think the alternative, which I think one of the other allogeneic CAR -T players are doing, is if you try to go head to head against established standard of care in second line, it's gonna be a very expensive trial, you know, if you have to do an RCT, versus either a TCE or another or an approved CAR T. And given the wealth of opportunities we have at CRISPR and our, you know, the number of things we're developing, we want to be very thoughtful about resource allocation.
So at this point, the, you know, where we may try to get to is third-line plus or relapsed refractory setting, you know, get that approval, get certain pockets of patients like such as the elderly population that cannot tolerate full cycles of approved frontline therapies, other patients that are ineligible for CAR -T for various reasons. And I think that'll expand the, the areas where, you know, once we get a label, we can always expand where we go, and especially in Europe, once we get a label, I think we'll get a lot of adoption because odds are we're gonna price this much lower than autologous CAR T. And for systems that-... you know, for the European systems, that's a huge benefit. You know, we'll actually get a lot of traction.
We're actually getting a lot of traction even in the Middle East, for instance, and you saw another allogeneic therapy approved in the Middle East recently. And that's because, you know, some of these systems cannot afford to provide an autologous CAR -T for every patient, and also, there's an issue of availability and turnaround, whereas an allogeneic CAR -T can get them similar, you know, efficacy for these patients, but much more convenient and cost-effective. So I think we just want to get on label. In fact, we're actually dosing patients in oncology in India, and that could, you know, that would never be possible with an autologous therapy or even the first-generation allogeneic therapies because the cost of goods are too high, and you wouldn't have any profit margin.
But given where we are with our cost of goods, it's actually a thing that, that's possible. And so, you know, there are significant markets outside the U.S. as well, where we could develop zugo-cel, and for us, it's all marginal returns because, you know, we're investing in zugo-cel anyways across autoimmune and oncology from a platform perspective. We're going to be making a lot of the drug. So if you can get on label, carve out niches in oncology that eventually could add up to $2 billion of revenue, that, that I think would be a very good strategy.
You mentioned pricing. You wouldn't price like the autologous CAR-Ts. How would you approach the pricing question if you get approval for zugo-cel in both, you know, the oncology space and the autoimmune space? What would be the approach there to harmonize-
Yeah.
-not?
Well, we think, you know, is that, you know, current autologous therapies in oncology are priced around $350K-$400K effective price, and the chatter is that in autoimmune disease, these therapies are likely to be priced even higher, you know, in the $700K-$800K range. I think for the systems, that's a pretty challenging setup. You know, agree that there's, you know, costs of treating these patients is high, et cetera, but if we're able to price our allogeneic CAR-Ts in the $200K range or slightly lower, I think we just increase access quite a bit. We still preserve margins, that will return-- you know, provide returns for shareholders and for the company and, and, and fuel further innovation.
But I think we just, you know, we'll be able to access that many more patients if we're able to do that in the Western markets. I think our pricing, you know, in India and parts of Asia and other, other markets, we'll have to think of, you know, even lower-cost manufacturing there, which we're in the process of doing, if we establish manufacturing there, that allow us to price even lower.
Okay. In the last few minutes, can we just touch on the in vivo CAR-T? You mentioned the two flavors, the transient and the permanent. Can you speak to those a little bit, and then where you're going there?
Yeah. I mean, this seems to be a very hot area right now. You know, I think the unlock essentially has been that, you can deliver these, cargo, whether it's mRNA encoding the CAR or, editing machinery into T -cells in the body, using either viral vectors or LNPs. And, our strategy in the space has been, twofold. With... We're firmly entrenched on LNPs versus viral vectors, because I just think that eventually, LNPs are going to win out. These are much more deterministic in how you manufacture them, much more reliable, and the biological effects that you see are less stochastic than viruses, where you may have safety events, or you may have unwanted integration or unwanted, activation, essentially. So we're, we're firmly, putting efforts into LNP-mediated delivery, and then we have two efforts.
One is LNP-mediated transient CAR, where we've engineered the mRNA that encodes the CAR in such a way that it's much more persistent and durable. So instead of a lot of competitors who have 3-day or 4-day detection of CARs, we're likely to see much longer detection of CARs, potentially even greater than 10 days, and that'll lead to a more deep depletion of B cells, in this case, if it's CD19. And so that's our transient CAR strategy. We actually have other engineering elements as well of the transient CAR that improve the persistence of these CARs and enable expansion. But transient CAR is likely to be more effective for autoimmune indications than oncology. You know, in oncology, you may not get the level of expansion with transient CAR to see complete elimination of tumor cells.
So for oncology, we're developing permanent CARs. In other words, we're actually going to deliver the CAR as a donor template, plus the editing machinery to create fully integrated CAR Ts in vivo, and, you know, that's actually moving nicely as well. So we can. We have engineered elements where the DNA donor template is not immunogenic when we deliver it, and the CAR integrating machinery is efficient enough that we get a certain percentage of T -cells with the integration of the CAR. And that will be game-changing in oncology, right? If you can do no conditioning, one injection, and have permanent CARs, you will completely eliminate the tumors, and that actually could work for a lot of solid tumors as well, because you could potentially think of more than one target in that case that you go after.
You know, in a way that's relatively safe as well. I think, you know, data will tell over time, but we're pretty excited about both these platforms, and we're doing the engineering to make them best in class on both fronts.
With the non-viral integrating, you would get essentially stable CAR production indefinitely in the immune lineage? Or would it still have some erosion over time if it was lost from the genome, you know, or something like that, or what is the timeframe?
Yeah, I mean, I think you will. There is a risk of B-cell aplasia, because you will have permanent production of CAR from these T-cells. Now, what you see with autologous CAR Ts is, yes, you get permanent T-cell, you know, editing of T-cells, but eventually, if the target's gone, they kind of go away. The T-cells quiet down, and then they just get eliminated, and they die, and they don't, you know, you don't have permanent B-cell aplasia. In this case, you have to make sure that the same effect is what you see with the permanent CARs, and that they do their job. You know, if it's in the case of CD19 or whatever, they get rid of all the CD19 positive cells, and when there's no antigen, the cells-
Yeah
You know, either go through autophagy or something else to just get eliminated, and they don't, you know, you won't have a permanent B-cell depletion effect.
But you can still do all the edits, the Regnase, and the base probably, all that can happen with this in vivo approach. Is that correct?
Yeah. We probably will pick different edits-
Okay
Than Regnase, because I think, you know, we want to be. You know, safety is our most concern. We want to make sure that we don't turbocharge these CARs either, given they're permanent, but we can actually make those edits in a slightly different way. You know, these include using shRNA and other elements to have the same effect on editing, without multiplex cutting of the genome.
Right. Got it.
I mean, in some way, it's not that different from, as Sameer, autologous CAR, where you have permanent integration of the CAR. But over time, the T-cells do exhaust, so even if they might be detectable, they're not actually active, and some patients, they're not even detectable anymore. And because they're actually now native cells, they're not allogeneic cells, you don't necessarily need the potency edits that you do with allogeneic cells, but the data will sort of drive things like that.
Yeah. Yeah. Okay. Okay, well, this was a short session. We didn't cover a lot of other things in the world of CRISPR related to your cardiovascular programs and your other diabetes programs and others, so we'll have to come back to that on another session. But this was a good, very, very helpful and enjoyable, so thank you both. Thank you.
Thank you for having us.
Thanks for having us.
All right.