Thanks to everyone for joining us. My name is Yanan Zhu. I'm one of the biotech analysts here at Wells Fargo. Today, we're privileged to have Sana Biotechnology joining us for a fireside chat, and with me is Steve Harr, President and CEO of the company. Thank you for joining us.
Yeah, Yanan, thank you for having me. Thank you, everybody, for joining us this afternoon, and appreciate Wells Fargo inviting us.
Great. Great. So I'm wondering if we can start with a couple of platform overview questions. What is Sana's core expertise? What are the therapeutic modalities and areas that you hope to make a difference with your technology?
Yeah, so I'm just gonna start. I'm gonna let you guys know we're gonna make forward-looking statements, and if you wanna, like, read our risk factors in Form 10-Q, that would be great. We try to outline for you a lot about our business. So we, you know, we started the company with the goal or the idea that one of the most important advances in medicines over the next several decades will be the ability to use cells and modify genes as medicines. And so we went about, you know, trying to go tackle what we thought were relatively tractable challenges within that, but important barriers to really success. And so, we really built the company around. I'll call it two main platforms and two things that came with it, right?
So the first insight was that if you really want to be able to, to transplant cells in the body or modify cells, we're gonna have to figure out how to overcome the barriers to allogeneic rejection, right? If I put my cells in you, your immune system is gonna reject them. And so that was really the beginning of the company, one of the core technologies. And what comes along with that is if you really want to do a lot of different cells, you have to understand how to turn pluripotent stem cells into differentiated cells predictably and at scale. And so we built a lot of capability around pluripotent stem cells. So platform number one is really this Hypoimmune platform, we call it, or hiding cells from the immune system.
Platform or insight number two is you can more or less do anything you want to, to a cell in a Petri dish, right? You modify the gene, change the RNA, whatever. The real challenge has been delivering those reagents in the body to the right cells, right? We set around the second platform was around a gene delivery or an RNA delivery capability, right? Coming with that, we built a platform where we can really incorporate into that cell-specific delivery, we call them fusogens, the ability to deliver gene editing reagents, base editing reagents, things like that. The two real core capabilities that we started on are hiding cells, using cells as medicines, hiding them from the immune system. The second is around delivery. How are we hoping to move forward?
So since the advent of transplant medicine, you know, this is the issue, rejection is the issue. And there are a couple of areas where we've already made progress in transplanting cells, either autologous cells or cells with very significant immunosuppression. So those would be things like T-cells, where CAR T-cells work, or beta islet cells, where people do cadaveric islets. And those give us roadmaps around where to start. So the couple of places that we're really going after to start with are making T-cells at scale from an allogeneic source for blood cancers. Platform number, I call it therapeutic area number one. Making CAR T-cell, allogeneic CAR T-cells from donors, for autoimmune disorders, call that big therapeutic area number two.
The third is being able to turn to create Hypoimmune or immune-hidden pluripotent stem cells that we can make into beta islet or islet cells and use for Type 1 diabetes , therapeutic area number three, right? And then the last is to be able to deliver some of these gene-editing reagents, which you can talk about separately. But I think most people, because we have the nearest term data, around this cloak, this Hypoimmune technology, really focused on that and its applicability. Maybe take one last statement around it. I'm gonna be a little bit bold in what I say here. I'm pretty confident we've solved the problem of immune rejection for non-human primates. Right? I'm pretty confident we've solved the problem of immune rejection for mice. Pretty confident we've solved the problem for immune rejection for humanized mice.
The real key question is, then, do those data translate to people, right? That's what we're gonna figure out here over the next several months. If it does, I think we get to make a whole bunch of important medicines for patients. And that's where a lot of the questions or risks for the company really reside right now.
Great. Great. Steve, I want to follow up on what you said about solving-
Yeah
the problem with transplant, in animals, at least, right?
Yes.
So that, that is indeed a very, bold statement. So I think, you know, if I think about it, if there is such a way, then cancer would exploit it, because it will avoid recognition by the immune system. So, you know, but you, you did have very, strong data, and the system is based on CD47, right? So I, I think you even have, in some of the, you know, slides and, prior comments, you said this could be as good as autologous or even last longer than autologous as a potential outcome, right? What gives you the confidence that CD47 can enable a complete evasion from the immune system, given that the immune system is designed to find the things that-
Yeah.
don't belong, right?
So CD47, in and of itself, does not do that. Really clear. So if you look at, like, what where did this all start? So about 15 years ago, some of our scientists started working on this problem of immune evasion, and started out by thinking about the paradox of pregnancy. And the paradox of pregnancy is that each of us is half mom and half dad, and the only reason we're in this room together today is our mothers didn't reject us. At the same time, pretty much none of us would be a good candidate to donate an organ to our mothers. So the question is, what's different about that maternal fetal border? And that was really what started this, you know, the work, and you can reduce it most simplistically, the question to two arms of the immune system.
There's the adaptive immune system of B and T cells, and that is what we often hear about with vaccines and other things. That's relatively easy to control. People have been able to do this really since gene editing came about, and that is you knock out MHC Class I and Class II. To your point, the problem with that is, is that both viruses and cancer have figured that out, right? And so you'll often find that these cells have marked downregulation of MHC Class I and Class II. So what we evolved is a system to attack those cells, and that system is really predicated around natural killer cells, right? And that's been the, that's the innate immune system, right? That's been the challenge for the field for at least 15 years, as long as I've been in it, right?
And no one's really cracked that code. And so the key was the key insight here was that overexpression of CD47 will turn off natural killer cells, and it will turn off all of the natural killer cells in your body, not just some fraction of them. And we actually know that this works in some regards of people. There's in the history of humanity, there's been one cell type that we consistently transplant safely and effectively, that has efficacy that's pretty similar to the autologous cell, and that is the red blood cell. And what is true about the red blood cell? It expresses no MHC Class I , it expresses no MHC Class II , and it markedly overexpresses CD47, and in fact, as CD47 is modified and cleaved, it's what leads to clearance of our red blood cells, right?
So, it's certainly possible, that's why the question is there, that the humans have something that's not in non-human primates that will attack these cells. I think that's like, that's the question for the company, right? I think, like, no one's ever shown they can get non-human primates to, you know, cells to evade their own immune system. So there isn't, like, a precedent as well as it works some of the time or whatever. It's like it's never happened before. So we have to see if there is something else there. That's, I think your, your point is fair, right? Might there be something in the immune system? 'Cause every time you think you understand something, human immunology humbles you, right?
So we have to run the experiment, but I don't think we could have proven this in any greater way in the non-human setting. And, you know, to date, there is no component of the human immune system, the human, let's call it the human primate immune system, that isn't present in the non-human primate.
Right.
Or is present, sorry. It is present, yes, sir.
Right.
Yeah.
Got it. Yeah, that, that's very helpful. The red blood cell analogy makes a lot of sense.
It's really not why we did it. We didn't even think about it. It came up-
Right
really, as we were, people were noticing the toxicities to CD47 antibodies.
Right. Right, right.
Which is an antibody.
Exactly. Yeah. Yeah. Is there, along the same line of thinking, is there any safety risk associated with implementing this approach because the cells are presumably completely invisible to the host immune system?
Yeah, absolutely. There are at least theoretical concerns, right? And the theoretical concerns would be that they become viral reservoirs, right? So viruses can reside in these cells that are, you know, invisible to the immune system and replicate, right? And the second is that tumors can show up, and you can't get rid of them. One of the things that we know, first of all, you can eliminate T cells, pretty straightforward.
Mm.
Steroids, you know, for CAR T cells, Campath eliminates T cells. But also, some of the experiments that we've done in improving the mechanism and also in creating a safety switch is if you give an animal CD40, or you give, or you put—add CD47 to a Hypoimmune study, that the cells are eliminated by natural killer cells. And that gives you both proof of concept on the mechanism, and it gives you a potential safety switch as well. The other, pluripotent, like, taking a pluripotent stem cell and making it a differentiated cell is, it's complicated, right? And genomes are every time our cells divide, on average, we have one mutation. Usually, it's in a non-coding region, doesn't matter, right?
But when you make trillions and trillions of cells, like our body, you know, you may run into a problem. That's how we end up with some randomly, with sometimes the tumors. And one of the, it's possible that this could happen with a pluripotent-derived cell as well. So we've engineered a second safety switch into every one of those cells, where with an approved small molecule, you know, we can kill the cell, hopefully. So I don't think it's a trivial question. I think anybody who makes an immune-hidden cell will have to grapple with this, with both kind of physicians who understand the field and with regulators. Hopefully, we've, the most important thing we can do, always, I can, and maybe I'll go on, I think. It's a three-pronged solution to any of these things.
The most important thing you can do is work as hard as you can to create cells that won't become cancerous, right? Second thing you can do is invest in tools so that you can diagnose any problems really early, right? The 3rd thing you can do is put in safety switches and things like that to eliminate the cells if they do become problematic, and we've tried to go through all three of them. It's not something we often talk about, but it's an important question.
Great. Yeah, thank you for the color there. Maybe let's talk about SC291 for B-cell malignancies. There are multiple edits in this cell therapy. What is the metric on chromosomal translocations? Because when multiple edits happens, there is that risk.
Yeah. I'll provide people a little bit of color to start right around. This is a great question. SC291, just to start, this is an allogeneic CAR T cell where we put in our Hypoimmune edits, and then it's targeting CD19. We put a CD19 CAR in it, right? So it targets CD19 on a cell. CD19 is expressed on normal B cells as well as on a host of B-cell malignancies, right? So that's the context. What we do is we when we make our Hypoimmune CAR T cells, we knock in two genes, the CAR and CD47, which you overexpress, and we knock out three genes.
We knock out, so we do some way in disrupting TCR alpha, so you can prevent graft-versus-host disease, my immune system trying to kill you. And then we knock out MHC Class I and Class II. Basically, your immune system recognizing my cells, right? And so we have to do all that. So it's three gene knockouts, two that go in. So first thing, chromosomal translocations happen all the time. So in order to really understand, anybody tells you that they don't see chromosomal translocations in their product, you should just say, "You don't run your assays very well," because you will find them at a background rate in dividing cells, right? So then the second question is, so you have two different, three different kinds of translocations you could have.
You can have on target to on target, TCR alpha to beta-2 microglobulin. I will tell you, who cares? Like, what bad can happen there, right? It's just like, it's just, it's just, It doesn't really, it doesn't look pretty on a screen, but there's nothing biologically that has effect. You can have on target to off target, right? This is why your off-target gene editing really, really matters, 'cause as soon as you start targeting different areas, you're going to see some chromosomal translocation. Specificity of gene editing agents is really, really important. Your on to off is really important. You have to look and say, okay, off to off. All right, that's the third plate thing that you can have.
It's like not on target, it's just to, That could either be random, and that's your background rate, or it could be specific. So you have to run it a bunch of times so you can figure out, is this specific or is this just one of these random things that happens at the background rate? So this is t o really do this well is an incredibly intensive analytical genomics and computational biology exercise. You can probably get away with doing it sloppily for some period of time, but my guess is that will catch up with you. So, whatever, I've read some things where people say they have zero off, they have zero translocations, and so you didn't look.
You didn't look well enough because if you just took autologous CAR T cells and divide them with no gene edits at all, you'll find them, right? You'll find them at the background rate. They just happen. Our chromosomes, when you're dividing, are always breaking and coming back together again.
Yeah.
Sometimes they come together again in a way that isn't what was intended.
Got it. That, that's a very helpful perspective. So essentially, by having highly specific cuts, you can lower the-
Risk
risk.
To be very clear, like, we actually published this stuff in ASH last year. We're very transparent. We have on-to-on translocations. They happen. We monitor them. We're gonna look at them as part of our release criteria. We don't want to see more than t hey happen at an infrequent rate, but they happen. And there is no way that you possibly could get around that other than not breaking DNA, but you'll still have some, right?
Yeah.
So, I would bet you like, so if you start to get into now doing two or three more gene edits, I think you might be in a place where you're a little less comfortable.
Got it. Got it. Is the CD47 introduced as an insertion into one of the cuts, or is it introduced with the lentivirus?
So we thought a lot about this, for right or for wrong. So lentivirus. Lentivirus uses HIV integrase. HIV integrase has been knocking genes into cells, into T cells, and we probably now have globally, I don't know, 100 million patient-years of experience. As far as I'm aware, it's never caused a T cell malignancy. Within lentivirus in CAR T cells, you have tens of thousands of patients a year of insertion. As far as I'm aware, it's never caused a T cell malignancy. If you just take like transposases or something where you put it in randomly, one of the first places it was done, three of the first six patients developed a malignancy. So there's something about this that isn't random, that seems to be relatively well-tolerated by T cells.
So we just felt like even though lentiviral is, like, not perfect and you're already cutting it, it's a safer way for patients. And over time, we may choose to do cell gene insertion into one of these sites, with different programs, but this just felt like a better, safer way to go for patients.
Got it. Got it. Thanks for explaining all the background. That's super helpful. Could you talk about Phase I ARDEN study? You know, the design of it, and when might we see first readout of data?
So, ARDEN study. We're developing the CD19 CAR T cell in B-cell malignancies first, and we'll go into autoimmune disorders shortly. The ARDEN is the oncology hematology. So that study, the primary goal at the outset is to find a safe and effective dose. And then the second goal is to figure out, does this stuff really work well, right? The third is to get yourself set up for your regulatory study. So the patient in the ARDEN study is like a lot of phase I studies. It's a dose-finding study. So it's three patients per dosing cohort, assuming no dose-limiting toxicity, and we have three doses, 60, 120, 200 million cells.
If you look at the approved CD19 autologous CAR T cells, they're all dosed somewhere between 100 and 200 million cells. Now, we're giving healthy volunteer cells, so there's some chance that 60 million is the right dose because they're just more potent than a cancer patient's. We also, you know, speed these things up, and who really knows? It's some chance 200 is the right dose, right? So it could be anywhere in there. So assuming no dose-limiting toxicity, you do one patient per month. Let's say every 28 days, you can enroll somebody, for 3, and then you get to go to the next dose, you do that again, right? You have, like, all these studies the same. If there's a dose-limiting toxicity, you enroll 6 at that dose. That's just how that works.
So I think about when you think about how do you interpret the data, so what's the most important question? Like, for me, the most important question is, do the data we've seen in animals, which has shown we can overcome immune recognition, translate to humans? That's relatively easy to figure out, right? So this is how at least we've thought about this. When we make these cells, about 85% of the CAR T cells have complete all the genetics in them. So what you've seen in the allogeneic field today across the board is patient's immune system is suppressed with some kind of lymphodepletion, maybe something else. The immune system comes back, and the immune system kills these cells, right?
So if our system works like we think it does, what should happen is patient's immune system goes away, CAR T cells grow, the immune system comes back, and it kills the 15% of cells that aren't fully edited, and the 85 keep going. And so what you should see is that 100% of cells that survive are fully edited cells. If you see that, you've pretty much proven the technology works because what you've shown is that the cells are surviving in the context of an intact immune system, right? That would be transformative. To me, that's most of the risk. That's relatively simple to find out, right? So the second question then becomes, well, do these guys make good CAR T cells? We have good people. I hope we do.
I think you figure that out by when you get to a, you know, a good dose. Do you see efficacy, right? Complete responses and things early. And do the cells persist? Because persistent, like, cells that last for a long time, which you need to kill, clear the tumor, have two elements to it. One, do you overcome immunology? Well, we already answered that question. And do you make really good T cells? That's the part we have to answer, right? So that we'll figure out when we get to the right dose, and you watch patients for some period of time, 3-6 months, let's call it. So that'll take a little longer to figure out.
The third is to say, okay, if you have, if you kill tumor and it sticks around for a while, does that lead to a differentiated clinical, long-term clinical response rate, durable CRs, right? So that requires you to enroll a ton of patients because statistically, there's really no difference between three out of four and three out of eight, right? So you got to get to a lot of patients and follow them for at least six months, right? So that's like back half of next year, right, when you figure that out. And I always think, well, then the fourth thing you want to know is, okay, fine, you made a great product with, you know, your CAR T cells. Can you do this across multiple donors and make a consistent product? That will take us, you know, a couple of years to figure out.
So we'll peel back that onion over the next few years. Almost all the risk is in the first question, right? Do you evade the immune system? The rest of it, we'll probably figure out. It's almost, you know, I think that's, it's not zero risk, but it's almost allowed.
On the first question, though, do you need a certain amount of time to be confident that you are indeed completely evading the immune system as opposed to some survival advantage, but over time, the cell is still being cleared, right? So what kind of follow-up do you think is-
I think you need much time. So lymphodepletion, first cell back, natural killer cell, 10 days. Second cell, the T cells are back within 2-3 weeks. Every single allogeneic cell that's been put in people today is gone by a month, or, or they're gone by the time that the immune system is, is back, right? If there's a. they more severely a suppressed immune system. So like, there is no magic thing that pops up later in the immune system, right? So would you feel better? I'm sure over time, we will. It would also, you could, we could evade the immune system and still make really bad T cells that die 'cause they exhaust. So
The more time you have and you see these things, the better you'll feel. But I think if you're at 100%, you've more or less said it's working, right? It's killing everything that's not gene-modified, right? So I think, you know, again, everybody has their own hurdle for belief. I think from a transplant immunology perspective, you've won.
Okay.
Right? Oh, yeah.
Got it. Got it. I see. So when we-
And by the way, we have a second experiment coming this year, which is in, we hope, right? We have to, we still have to get through a little bit, which will be transplanting these immune-modified cells as primary immune-modified cadaveric islet cells and transplant them into Type 1 diabetics .
Right.
You know, there, the patient has not only attacked immune system, they have an autoimmune reaction to beta cells, right? So those cells are typically rejected within a week. You do need a little bit of time, right? It's not like day 1. But if these cells are living at 3, 4 weeks, our immunologist say, two, nothing's gonna get them.
Got it.
There's no immunosuppression. It's just put the cells on board.
Got it. So for you, you have an investigator sponsor?
Absolutely, yeah.
Right. So that one, it's like a islet isolate that you're Engineering and then putting back. This is not the iPSC. It's a cadaveric islet cells. So for that one, I was wondering, the transduction, the efficiency of editing, because it's not in suspension.
Yeah.
Right?
Well, that's actually, that's an assumption of yours. But like, let me explain what we do. So for the last, let's call it 15, 20 years, it started up in Edmonton, Canada, someone figured out how to isolate. So to take a step back, Type 1 diabetes , the immune reaction kills the patient's pancreatic beta cells. Beta cells live in pancreatic islets, right? Which is just so what they figured out is if you isolate islets from cadavers, people who have recently died, and transplant those into a patient with Type 1 diabetes , and you have significant immunosuppression. In a large percentage of them, you will cure their Type 1 diabetes . They can live off insulin for years, right?
What we're trying to do is take these same gene edits that we've done and, you know, knock down class one, knock down class, knock out class two, overexpress CD47, and apply that to the same protocol, primary cadaverically-derived islets, and transplant them in a patient. The goal is euglycemia, so normal blood glucose, without insulin over time. Not for this study, but that's what you want to do over time. We've done this in non-human primates, right? It works. We're trying to do this in humans. What we do is, first off, you have to knock genes out and knock one into a non-dividing cell. It's actually not simple to do. Most of the time, you see when these things are done, it's in dividing cells.
The second thing is, you're right, these cells exist in clusters, but you put them, you break the cluster, and you put them into single cells. It's the only way you can gene edit efficiently, and then you recluster them. It works, right? That's, it's what's actually done in these protocols, for example, when they take an islet, and they cryopreserve it, people cryopreserve as single cells, and they recluster them and put them back together again. So it seems that these islets have a natural affinity to create themselves and come back together again. But you have to do, you don't do it in vivo. You have to do it, you do it, you know, as part of the manufacturing process.
Right. Could you talk, disclose the percent of cells edited? 'Cause that one thing that I was wondering is, say, if you have 80% edit, there are 20% of the cells in the islet that still have the antigen.
Yeah.
And, yeah.
So this is different than the CAR T. In the CAR T program, the primary safety effect that, you know, regulators are always worried about is knocking out enough of the TCR alpha, so you prevent graft-versus-host disease, again, my immune cells trying to kill you. And so you select everybody in the field selects for cells that have been gene-modified there. So what we're doing here, to your point, we don't have 100% editing of, like, knockout of MHC Class I , is we're selecting for cells that have MHC Class I knockout. So we're very close to 100%, MHC Class I knockout. And then, you know, part of the release criteria is CD47 overexpression. Those cells, if they don't express enough, they will just be eaten up by natural killer cells. There's no way around that.
Right.
But they still won't hit the cells around them, right?
Okay.
We wouldn't want to create a B or T cell to our program today.
Got it. I see. I see. Good to know that even if there is some immune infiltrate, initially, those immune cells wouldn't harm the-
Yeah
the edited cells.
Again, it works in non-human primates, so, I will say this, like, what kept me up about doing this, our team really want to do this, was I can't think of a way you could have a false positive, meaning if this works, which I'll talk about how we define working, it will translate into the iPS setting. The risk is false negative. Like, for some reason, to your point, we don't fully edit these or things happen because it's just not as rigorous of a manufacturing. You know, it's just not as rigorous of a gene editing process that it would be a false negative to what will happen in the iPS derived products. We have to really work hard not to end up with a false negative.
Got it.
The way I think about. By the way, we've thought about this working is, you want to see. The real question here is not do cadaveric islet cells make enough insulin to treat patients? Because that's not our drug. The real question is, do our gene edits evade allogeneic and autoimmune rejection, right? And that's what we're trying to look at. So because you're also at the beginning of a dose-finding for a novel drug. So the first question you can ask is, do you see cell survival by imaging and no evidence of immune killing, immune response? You won. That's true. I think the better level of evidence for many people, though, would be looking at C-peptide levels.
So the way that our beta cells make insulin is you make something called proinsulin that is cut by an enzyme into C-peptide and insulin and secreted. So Type 1 diabetics have no C-peptide in their blood that's detectable. So if you see stable, detectable C-peptide, you have stable, functioning beta cells by definition. You have one, right? There's some chance we actually, you know, decrease or even get rid of the patient's need for insulin. You know, the first doses of that are less likely. From my perspective, there's zero difference in those two in what we learn, what we're trying to do, and in the value of the company. My guess is, though, headlines, people will like it if it's so valuation might be different, but value will be no different.
Got it. Got it. One of the things I was also wondering is about the intramuscular implantation route.
Yeah.
Has that been de-risked, as not being a thing that prevents you from seeing a positive signal?
Yeah. So the way that cadaveric islets have traditionally been, or most frequently, put into the body, and the way that, you know, the companies who are doing pluripotent stem cell-derived islets to put in the body is into the liver. So there's a large needle under radiologic that's put into the portal vein. It's injected, the cells are injected, and they kind of disseminate through the liver. There are kind of three issues with that. One is you get this thing called immediate blood-mediated immune response, and it will kill the majority of the cells right away. It's not great, right? The second is that you can't find these cells if something goes wrong because they're all over the liver.
The third is, it's like, it's a pretty, it's not a juicy, dangerous, but it's not an insignificant thing to be doing this under interventional radiology. It's not that scalable, right? There's increasing use in humans of putting the cells in, intramuscularly, you know, into somewhere like the arm. It's also something that we've done in the preclinical setting. To be clear, it is not as well validated as what's being done in the liver. We're doing it because we think it's the better, safer route, but it's not a zero-risk decision, right? It's a fair question.
Got it. Got it. Thanks. I was wondering, you know, for then switching to the BCMA CAR T, for example, a lot of the allogeneic CAR T players are reevaluating their product candidates. And for you, you know, what is the bar for allogeneic CAR T? Obviously, the key thing here is that Carvykti, Carvykti is very potent. Do you think an allogeneic BCMA CAR T has to match that efficacy?
Yeah.
Um, yeah.
Like, you know, our goal is really simple: make allogeneic cells are at least as good as autologous cells and to do them at scale. So we have three targets, CD19, where there's a high bar, CD22, where there's data, but you know, we're as far along as anybody else in turning it into a drug for CD19 failures and BCMA. Might there be a market, and we're forced to come back and talk about it if these don't work as well? Yes. It just isn't what we're trying to do. And so with each of them, we've also licensed because it's the CAR that's really important, right? It's not just the target. So what you've seen is CD19 is relatively easy, right? CD22 is hard. It's a big, floppy cell surface protein, and BCMA is relatively hard, right, where the CAR and the binder really matter.
So in this case, what we licensed is a drug that has, you know, over 100 patients worth of data. It has a, In the CAR T naive population, it has a 96% MRD negativity rate. It has over 80% of patients that are MRD negative at 1 year. These are really good data that are as good as anybody else's generated in the autologous field. I think BCMA, multiple myeloma, has been a space where CAR T-cell persistence is even more important than it maybe has been in the CD19 setting. And so we have to make sure we've done well enough in CD19, right, with the persistence to really make it a valuable investment with BCMA.
But I think, you know, so you have to make a great CAR, overcome immunologic rejection, and actually have a great T cell, too, to make it worthwhile. But I don't know why our bar would be to try to make a drug that wasn't as good as the best-in-class. I don't think that's the right thing to do for patients.
Great. Great. I know we're out of time, but I do have a question that I think is very important and that I'd really like to ask you. That is, your in vivo HSC approach, which has implication for sickle cell, in vivo sickle cell treatments approach, that will be a huge, humongous opportunity. But other companies are using LNPs and using antibody-coated LNPs. What do you think in terms of who will win that - this race for this? You know, what , why is your fusogen approach-
Yeah
a better approach?
Well, to date, I'll say a couple things. One, LNPs, they bind. They basically, it's a lipid, it binds to ApoE, it goes to wherever the LDL receptor is, right? You can kind of change the protein it binds to, and it goes to a receptor. So the challenge is they're not specific at all, and you've even seen this in some of the context of what people are talking about recently. They get into cells around in your reproductive organs, right? And so the question is then, are you going to have. At least for the near term, people have been concerned, are you going to be changing gamete cells, right? I don't know the answer to that. We don't study it. Second thing, so that's the big risk, because the majority of those cells will always go to the liver, right?
The second question, the thing I'd say is, since I've been doing this, I think LNPs have done better than I thought they would do, and I think some of these, like, kind of targeting things might actually work, so I wouldn't dismiss them, right? But what we have shown is that we can do cell-specific delivery. The carrier system that we use doesn't exit the blood, liver, bone marrow, spleen category, so you're not going to end up with organ toxicity or in the gamete cells and the reproductive organs. So that should work. We've shown you that we can get into HSCs. We've shown you we can deliver the gene editing agents at high efficiency. Like, we have, we're at the cusp of where you think you need to be to be really efficient.
I think in sickle cell, from the transplant literature, what it says is you have to change at least 20% of the long-lived HSC cells to have the phenotypic response you want to have. We may be there, we may not be, and we're running those experiments. If we are, it's a pretty straightforward path. If we're not, we have more work to do. I generally agree, it'd be really, really. The only way you're going to make this accessible to, you know, large parts of the world, the vast majority of people with sickle cell, is you can't ask them to undergo basically an allogeneic bone marrow transplant level of chemotherapy. You're going to have to give them a therapy that you can deliver safely and effectively without one month of intensive hospitalization, right?
Right.
And we'll see if we can make that happen or not. I like you, share the enthusiasm for where it is. Like you, we keep an eye on the LNPs and other things. Like, I don't know who will win. I'm pretty sure if we get it right, we'll have plenty of patients to treat, and we'll have to watch them. The other thing I would say is, with LNPs, they do have a relatively small carrier, payload they can carry, compared to what we're doing, so it will just depend on what technology you're trying to deliver.
Right. Got it.
If you get it there, if you get it there, be relatively specific and have the right, payload.
Yeah. Got it. Thanks for all the details and background and color. I, I really, really appreciate it.
Yeah, thank you, and thanks, everybody, for your time and attention. Enjoy the afternoon. Bye-bye.